AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Azaspiracid-1

 Uncategorized  Comments Off on Azaspiracid-1
Sep 302016
 
str1
 Azaspiracid-1: sc-202482...
AZA-1
Application:An activator of JNK and cell growth inhibitor
CAS Number:214899-21-5
Molecular Weight:842.1
Molecular Formula:C47H71NO12
Image result for waitThe presentation will load below

 str1str2
str1
Thivisha Rajagopal 
Thivisha Rajagopal

Thivisha Rajagopal scored 13 on the Biological Sciences and 12 on the Physical Sciences sections of the MCAT. Thivisha has completed a B. Sc. in Medicinal Chemistry and an M.Sc. in Chemistry. Thivisha is passionate about teaching Organic Chemistry and she has been a Teaching Assistant for Organic Chemistry I and II for the past two and half years. Thivisha has also been tutoring students in General Chemistry, Organic Chemistry, and Biochemistry for over 10 years. In the classroom, Thivisha is very informal and likes to build a healthy and comfortable relationship with students. She believes it is very important to allow students to interact in discussion with their peers and the teacher.

Education

2010, M.Sc. [Chemistry]
2007, B.Sc. (Honours) [Medicinal Chemistry]

Teaching Experience

2009-Present, Lecturer, Chemistry
2009-Present, Lecturer, Biology
2008-10, Lecture TA, Organic Chemistry
2007-8, Lab TA, Organic Chemistry
1999-2010, Private Tutor, General Chemistry, Organic Chemistry, Biochemistry

Thivisha RajagopalEmail: traja085@hotmail.com

Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, ON, K1N 6N5, Canada

Azaspiracid-1 is an activator of JNK (c-Jun-N-terminal kinase)and caspases. It is a cellular growth inhibitor and inducer of cytoskeletal alterations. Azaspiracid-1 is also a modulator of intracellular cAMP (cyclic adenosine monophosphate) and calcium levels. It acts as an inhibitor of cholesterol biosynthesis in human T lymphocyte cells. Azaspiracid-1 is a potent teratogen to finfish and also acts as a cytotoxin to mammalian cells. 

References

Multiple organ damage caused by a new toxin azaspiracid, isolated from mussels produced in Ireland: E. Ito, et al.; Toxicon 38, 917 (2000) Azaspiracid-1, a potent, nonapoptotic new phycotoxin with several cell targets: Y. Roman, et al.; Cell. Signal. 14, 703 (2002) Teratogenic effects of azaspiracid-1 identified by microinjection of Japanese medaka (Oryzias latipes) embryos: J.R. Coleman, et al.; Toxicon 45, 881 (2005) Cytotoxic and cytoskeletal effects of azaspiracid-1 on mammalian cell lines: M.J. Twiner, et al.; Toxicon 45, 891 (2005) Azaspiracids modulate intracellular pH levels in human lymphocytes: A. Alfonso, et al.; BBRC 346, 1091 (2006) Cell growth inhibition and actin cytoskeleton disorganization induced by azaspiracid-1 structure-activity studies: N. Vilarino, et al.; Chem. Res. Toxicol. 19, 1459 (2006) The c-Jun-N-terminal kinase is involved in the neurotoxic effect of azaspiracid-1: C. Vale, et al.; Cell Physiol. Biochem. 20, 957 (2007) Effects of azaspiracid-1, a potent cytotoxic agent, on primary neuronal cultures. A structure-activity relationship study: C. Vale, et al.; J. Med. Chem. 50, 356 (2007) Irreversible cytoskeletal disarrangement is independent of caspase activation during in vitro azaspiracid toxicity in human neuroblastoma cells: N. Vilarino, et al.; Biochem. Pharmacol. 74, 327 (2007) Transcriptional profiling and inhibition of cholesterol biosynthesis in human T lymphocyte cells by the marine toxin azaspiracid: M.J. Twiner, et al.; Genomics 91, 289 (2008)

 

Total Synthesis of (+)-Azaspiracid-1. An Exhibition of the Intricacies of Complex Molecule Synthesis

Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138
J. Am. Chem. Soc., 2008, 130 (48), pp 16295–16309
DOI: 10.1021/ja804659n

 

Abstract Image

The synthesis of the marine neurotoxin azaspiracid-1 has been accomplished. The individual fragments were synthesized by catalytic enantioselective processes: A hetero-Diels−Alder reaction to afford the E- and HI-ring fragments, a carbonyl-ene reaction to furnish the CD-ring fragment, and a Mukaiyama aldol reaction to deliver the FG-ring fragment. The subsequent fragment couplings were accomplished by aldol and sulfone anion methodologies. All ketalization events to form the nonacyclic target were accomplished under equilibrating conditions utilizing the imbedded configurations of the molecule to adopt one favored conformation. A final fragment coupling of the anomeric EFGHI-sulfone anion to the ABCD-aldehyde completed the convergent synthesis of (+)-azaspiracid-1.

str1 str2

(+)-azaspiracid-1 (ent-2) (5.4 mg, 90%) as a white solid. TLC Rf = 0.25 (25:75 MeOH/EtOAc);

[α] 24 D +21.7 (c 1.00, MeOH);

IR (film) 3301, 3175, 3000 (br), 2957, 2927, 2872, 1774, 1731, 1581, 1459, 1439, 1408, 1379, 1318, 1267, 1242, 1223, 1199, 1143, 1127, 1069, 1044, 1023, 984, 875, 862, 840, 805, 734 cm−1 ;

1 H NMR (600 MHz, CD3OD, AcOH added) δ 5.78-5.71 (m, 2H, C8H, C4H), 5.64 (bd, 1H, J = 10 Hz, C7H), 5.47 (dd, 1H, J = 15, 7 Hz, C5H), 5.36 (d, 1H, J = 1 Hz, C44Ha), 5.18 (d, 1H, J = 2 Hz, C44Hb), 5.03 (t, 1H, J = 4 Hz, C34H), 4.81 (app bd, J = 2 Hz, C6H), 4.43 (td, 1H, J = 9, 6 Hz, C19H), 4.37 (bd, 1H, J = 3.5 Hz, C32H), 4.24 (bs, 1H, C17H), 4.09 (d, 1H, J = 3 Hz, C33H), 4.00 (d, 1H, J = 10 Hz, C25H), 3.93 (d, 1H, J = 5.5 Hz, C20H), 3.91 (bd, 1H, J = 2 Hz, C16H), 2.91 (bdd, 1H, J = 12, 3 Hz, C40Ha), 2.83 (t, 1H, J = 12 Hz, C40Hb), 2.66 (dd, 1H, J = 15, 4.5 Hz, C35Ha), 2.50 (d, 1H, J = 15 Hz, C35Hb), 2.51-2.47 (m, 1H, C9Ha), 2.43 (d, 1H, J = 14 Hz, C27Ha), 2.37-2.30 (m, 5H, C3H2, C11Ha, C2H2), 2.26 (d, 1H, J = 14 Hz, C27Hb), 2.27-2.22 (m, 1H, C30H), 2.19-2.09 (m, 3H, C12Ha, C9Hb, C22H), 2.09-1.95 (m, 6H, C29Ha, C14H, C18H2, C37H, C12Hb), 1.93-1.89 (m, 1H, C39H), 1.88-1.83 (m, 2H, C31Ha, C15Ha), 1.76 (app dt, 1H, J = 14, 3 Hz, C15Hb), 1.72-1.69 (m, 1H, C38Ha), 1.68 (dd, 1H, J = 12, 7 Hz, C11Hb), 1.53 (dt, 1H, J = 13.5, 5 Hz, C31Hb), 1.46-1.42 (m, 2H, C23H2), 1.40-1.27 (m, 3H, C29Hb, C24H, C38Hb), 0.99 (d, 3H, J = 7 Hz, C46H3), 0.97 (d, 6H, J = 6 Hz, C45H3, C47H3), 0.96 (d, 3H, J = 6 Hz, C41H3), 0.92 (d, 3H, J = 7 Hz, C42H3), 0.85 (d, 3H, J = 7 Hz, C43H3);

13 C NMR (125 MHz, CD3OD, AcOH added) δ 177.8 (C1), 148.4 (C26), 132.4 (C4H), 131.4 (C5H), 129.2 (C7H), 123.4 (C8H), 117.0 (C44H2), 111.3 (C13), 107.2 (C10), 100.2 (C21H), 98.7 (C28), 96.7 (C36), 81.6 (C33H), 79.6 (C25H), 79.1 (C19H), 78.2 (C16H), 76.7 (C20H), 74.8 (C34H), 73.3 (C17H), 72.8 (C32H), 72.3 (C6H), 49.2 (C27H2), 46.1 (C40H2), 44.1 (C29H2), 42.4 (C24H), 41.7 (C35H2), 38.2 (C23H2), 37.6 (C38H2), 37.5 (C12H2), 37.2 (C18H2), 36.7 (C22H), 35.7 (C9H2, C37H), 35.30, 35.25 (C2H2, C31H2), 33.2 (C11H2), 32.6 (C15H2), 30.9 (C14H), 29.3 (C3H2), 29.0 (C39H), 26.3 (C30H), 23.5 (C45H3), 18.5 (C47H3), 18.1 (C43H3), 16.6 (C41H3), 16.4 (C42H3), 15.5 (C46H3); Exact mass calcd for C47H71NO12 ([M+H] + ): 842.5054; found: 842.5023 (ESI).

http://pubs.acs.org/doi/suppl/10.1021/ja804659n/suppl_file/ja804659n_si_001.pdf

//////////Structural Elucidation, Total Synthesis , Azaspiracid-1,  Thivisha Rajagopal,  January 29, 2009,  University of Ottawa

C[C@H]1C[C@H]2[C@@H]3[C@@H](C[C@]4(O3)[C@H](C[C@H](CN4)C)C)O[C@@](C1)(O2)CC(=C)[C@@H]5[C@H](C[C@H]([C@@](O5)([C@@H]([C@@H]6C[C@@H]7[C@H](O6)C[C@H]([C@@]8(O7)CC[C@@]9(O8)CC=C[C@H](O9)/C=C/CCC(=O)O)C)O)O)C)C

Share

Total synthesis of a thromboxane receptor antagonist, terutroban

 Uncategorized  Comments Off on Total synthesis of a thromboxane receptor antagonist, terutroban
Feb 252015
 

Terutroban acid skeletal.svg

TERUTROBAN

UNII-A6WX9391D8, S18886, S 18886, 165538-40-9, triplion, Terutroban [INN]
Molecular Formula:C20H22ClNO4S
Molecular Weight:407.91098 g/mol
3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid

Terutroban is an antiplatelet agent developed by Servier Laboratories. as of|2008, it is tested for the secondaryprevention of acute thrombotic complications in the Phase III clinical trial PERFORM.

Method of action

Terutroban is a selective antagonist of the thromboxane receptor. It blocks thromboxane induced plateletaggregation and vasoconstriction.

Paper

Total synthesis of a thromboxane receptor antagonist, terutroban

Org. Biomol. Chem., 2015, 13,2951-2957
DOI: 10.1039/C4OB02302A, Paper
*Corresponding authors
aDivision of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, India 500 007
E-mail: srivaric@iict.res.in;
Fax: +91-40-27160152 ;
Tel: +91-40-27193210, 27193434
bAcademy of Scientific and Innovative Research, New Delhi, India
Org. Biomol. Chem., 2015,13, 2951-2957

DOI: 10.1039/C4OB02302A

3-(6-(4-Chlorophenylsulfonamido)-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)propanoic acid (2).
…………………….deleted……………………… to give terutroban (2) (1.12 g, 82%) as a white solid.
………………………………………………………
 1H NMR (300 MHz, DMSO-d6
δ 7.91 (d, J = 6.6 Hz, 1H),
7.84 (d, J = 8.5 Hz, 2H),
7.66 (d, J = 8.5 Hz, 2H),
6.87 (d, J = 7.7 Hz, 1H),
6.69 (d, J = 7.7 Hz, 1H),
3.31(m, 1H),
2.83–2.65 (m, 4H),
2.63–2.54 (m, 2H),
2.30–2.21 (m, 2H),
2.19 (s, 3H),
1.86–1.74 (m, 1H),
1.63–1.50 (m, 1H); 
……………………………………………………………………….
13C NMR (75 MHz, DMSO-d6
δ 174.2, –C=O-OH
140.7,
137.3,
136.9,
133.5,
133.3,
131.9,
129.5,
128.5,
127.9,
127.1,
49.0,
36.4,
32.9,
29.5,
24.3,
24.2,
19.2; -CH3
IR (KBr): νmax 2924, 1709, 1219, 772 cm−1;
HRMS (ESI): Calcd for C20H23O4NClS 408.1030 [M + H]+, found 408.1040.
[Reported 1H NMR  ref a (DMSO-d6) δ 12.5 (s, 1H), 7.9 (s, 1H), 7.8 (d, 2H), 7.7 (d, 2H), 6.9–6.7 (d, 2H), 3.3 (m, 1H), 3.0–2.5 (m, 6H), 2.3 (m, 2H), 2.2 (s, 3H), 2.0–1.5 (m, 2H).]
a   (a) B. Cimetière, T. Dubuffet, O. Muller, J.-J. Descombes, S. Simonet, M. Laubie, T. J. Verbeuren and G. Lavielle, Bioorg. Med. Chem. Lett., 1998, 8, 1375
Synthesis of terutroban (2) is achieved following a non-Diels-Alder approach using cost-effective chemicals.
PREDICTIONS
CAS NO. 165538-40-9, 3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid H-NMR spectral analysis
3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid NMR spectra analysis, Chemical CAS NO. 165538-40-9 NMR spectral analysis, 3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid H-NMR spectrum
CAS NO. 165538-40-9, 3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid C-NMR spectral analysis
3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid NMR spectra analysis, Chemical CAS NO. 165538-40-9 NMR spectral analysis, 3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid C-NMR spectrum
EXTRA INFO

Terutroban is an antiplatelet agent developed by Servier Laboratories. It has been tested for the secondary prevention of acute thrombotic complications in the Phase III clinical trial PERFORM (Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack).[1] The study was prematurely stopped and thus it could not be determined whether terutroban has a better effect than aspirin.

Method of action

Terutroban is a selective antagonist of the thromboxane receptor. It blocks thromboxane induced platelet aggregation andvasoconstriction.[2][3]

 

…………………..

 

10.1358/dof.2006.031.10.1038241

 

Thromboxane A2 (TxA2) is an unstable metabolite of arachidonic acid formed by the cyclooxygenase pathway and released from activated platelets, monocytes and damaged vessel walls, causing irreversible platelet aggregation, vasoconstriction and smooth muscle cell proliferation. From efforts to discover novel compounds that could block the deleterious actions of TxA2, the 2-aminotetralin derivative terutroban sodium (S-18886) emerged as a potent, orally active, long-acting, selective antagonist of thromboxane (TP) receptors. The agent was able to inhibit TP agonist-induced platelet aggregation and vasoconstriction and was selected for further development as an antiplatelet and antithrombotic agent. Terutroban has been shown to be effective in animal models of thrombosis, atherosclerosis and diabetic nephropathy and is currently undergoing phase III development for the secondary prevention of acute thrombotic complications of atherosclerosis.

 

 

References

  1.  Hennerici, M. G.; Bots, M. L.; Ford, I.; Laurent, S.; Touboul, P. J. (2010). “Rationale, design and population baseline characteristics of the PERFORM Vascular Project: an ancillary study of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack (PERFORM) trial”Cardiovascular Drugs and Therapy24 (2): 175–80. doi:10.1007/s10557-010-6231-2PMC 2887499PMID 20490906edit
  2.  H. Spreitzer (January 29, 2007). “Neue Wirkstoffe – Terutroban”. Österreichische Apothekerzeitung (in German) (3/2007): 116.
  3.  Sorbera, LA, Serradell, N, Bolos, J, Bayes, M (2006). “Terutroban sodium”. Drugs of the Future 31 (10): 867–873.doi:10.1358/dof.2006.031.10.1038241
Terutroban
Terutroban acid skeletal.svg
Systematic (IUPAC) name
3-((6R)-6-{[(4-Chlorophenyl)sulfonyl]amido}-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid
Clinical data
Legal status
  • Investigational
Routes Oral
Pharmacokinetic data
Half-life 6–10 hours
Identifiers
CAS number 165538-40-9 
609340-89-8 (sodium salt)
ATC code None
PubChem CID 9938840
ChemSpider 8114465 
UNII A6WX9391D8 
Chemical data
Formula C20H22ClNO4S 
Molecular mass 407.911 g/mol

 

 

Srivari Chandrasekhar

Chief Scientist & Head, Division of Natural Products Chemistry, CSIR- Indian Institute of Chemical Technology

Chandrasekhar obtained his Bachelor’s and Master’s degrees in 1982 and 1985 respectively, from Osmania University, Hyderabad and excelled in the same with distinction. He then joined A. V. Rama Rao’s group at CSIR–IICT and earned his doctorate in 1991, also from Osmania University. Between 1991 and 1994 he was associated with J. R. Falck (University of Texas Southwestern Medical Center) as a postdoctoral student. In 1994, Chandrasekhar joined his parent institute (CSIR–IICT) as a scientist

Tarnaka, Hyderabad, India 500 007

srivaric@gmail.com

 

READ………..http://www.currentscience.ac.in/Volumes/108/02/0160.pdf

Council of Scientific and Industrial Research
Ministry of Science and Technology, Government of India
CSIR-IICT
CSIR-Indian Institute of Chemical Technology





http://www.iictindia.org

 


Chandrasekhar obtained his Bachelor’s and Master’s degrees in 1982 and 1985 respectively, from Osmania University, Hyderabad
After obtaining a Ph.D. under the supervision of Dr. A. V. Ramarao at the Indian Institute of Chemical Technology, Hyderabad,
DR AV RAMA RAO
He moved to theUniversity of Texas Southwestern Medical School for post-doctoral research with Professor J. R. Falck
Professor J. R. Falck
and
then to the University of Goettingen, Germany as Alexander von Humboldt Fellow in the group of Professor L. F. Tietze.
 Professor L. F. Tietze
His research interests include the synthesis of marine natural products, peptides and peptidomimetics, combinatorial chemistry and new solvent media for organic synthesis.
He is a recipient of a Young Scientist award of the Indian National Science Academy, B M Birla Science Prize and National Academy of Sciences-Reliance Industries Platinum Jubilee Award. He has over 190 publications, 2 patents, and guided 20 students for their Ph.D. degrees. Presently he is a deputy director at the Indian Institute of Chemical Technology where he supervises a group of 30 researchers

Srivari Chandrasekhar, senior scientist, Organic Chemistry Division, Indian Institute of Chemical Technology (IICT), has been conferred Fellow of Indian Academy of Sciences, Bangalore.

According to a press release here on Tuesday, Dr. Chandrasekhar has been conferred the honour for his significant contribution in organic chemistry and medicinal chemistry.

The major contributions include synthesis of complex natural products, especially of marine origin with anti-cancer and anti-depressant properties, green chemistry and automation chemistry to make large number of new chemicals.

He has produced 25 Ph.D. students and published more than 200 papers in international journals. He is also a fellow of National Academy of Sciences.

Srivari-ChandrasekharIndia has achieved many prizes in 2014. Before the year ends IICT scientist Srivari Chandrasekhar has added one more prize, he wins Infosys Prize. The scientist who has made important contributions in potential drug developments. Srivari Chandrasekhar from CSIR-IICT , Hyderabad, was announced the winner of the Infosys Prize 2014 in Physical Sciences. The award includes a purse of Rs. 55 lakh, a 22 carat gold medal and citation. The award will be presented by The President on January 5 in Kolkata. The prize is awarded annually by the Infosys Foundation.

He had won the CSIR Technology award-2014 along with his team member

Chandrasekhar’s current contribution is to develop a technology for manufacturing Misoprostal, an abortive drug also used in the treatment of ulcers. Now we can easily get rid of Ulcer.

He has successfully prepared some important drug molecules such as bedaquiline for multi-drug resistant TB, Galantamine for Alzheimer’s disease, Sertraline for treatment of depression, Nebivolol for hypertension and marine natural products such as Eribulin, Azumamide, Arenamide and Bengazole which are scarce to get from nature, with potent biological activities.

As he moves on achieving his target , he has made contributions in synthesizing complex and scarcely available natural products in the laboratory using easily available chemicals.

Chandrasekhar has over 250 publications in national and international journals to his credit.

Prof. Chandrasekhar has displayed an exceptional flair for identifying and synthesizing molecules of biological relevance, topical synthetic interest and utility to industry. His research efforts, with an impressive degree of innovations and enterprise, have led to the synthesis of complex and scarcely available natural products and new molecular entities for affordable healthcare. His endeavors have provided cost-effective technologies to chemical industry through identification of new reagents / solvents for specific transformations. Chandrasekhar’s group has synthesized several classes of complex natural products in optically pure form employing chiral pool precursors and catalytic asymmetric reactions and his syntheses of pladienolide, azumamide, bengazole etc., bear testimony to the efficacy of such approaches.

His passion and commitment to topical health related problems is through provisioning for better and affordable access to important drugs. Mention may be made of hissynthesis of bedaquiline, the first drug approved by FDA after a gap of over 40 years for the treatment of multi-drug resistant TB through simpler transformations and higher yields to ensure ready availability. He along with a team atIICT has developed a scalable synthetic route for misoprostol (a hormone like biologically important synthetic prostaglandin) used to prevent gastric ulcer, induce labor and / or abortion (particularly for safe termination of unwanted pregnancies), which has already been commercialized.

Share
Jan 152014
 

File:Sirolimus.svg

Rapamycin (Sirolimus)

(3S,6R,7E,9R,10R,12R,14S,15E,17E,19​E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,​25, 26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-​[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]​-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-he​xamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacy​clohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone

Wyeth Pharmaceuticals (Originator)

M.Wt:914.18

Formula:C51H79NO13

53123-88-9 cas no

Antifungal and immunosuppressant. Specific inhibitor of mTOR (mammalian target of Rapamycin). Complexes with FKBP-12 and binds mTOR inhibiting its activity. Inhibits interleukin-2-induced phosphorylation and activation of p70 S6 kinase. Induces autophagy in yeast and mammalian cell lines.

Rapamycin is a triene macrolide antibiotic, which demonstrates anti-fungal, anti-inflammatory, anti-tumor and immunosuppressive properties. Rapamycin has been shown to block T-cell activation and proliferation, as well as, the activation of p70 S6 kinase and exhibits strong binding to FK-506 binding proteins. Rapamycin also inhibits the activity of the protein, mTOR, (mammalian target of rapamycin) which functions in a signaling pathway to promote tumor growth. Rapamycin binds to a receptor protein (FKBP12) and the rapamycin/FKB12 complex then binds to mTOR and prevents interaction of mTOR with target proteins in this signaling pathway. Rapamycin name is derived from the native word for Easter Island, Rapi Nui.

  • (-)-Rapamycin
  • Antibiotic AY 22989
  • AY 22989
  • AY-22989
  • CCRIS 9024
  • HSDB 7284
  • NSC 226080
  • Rapammune
  • Rapamune
  • Rapamycin
  • SILA 9268A
  • Sirolimus
  • UNII-W36ZG6FT64
  • WY-090217
  • A 8167

A macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to IMMUNOPHILINS. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties.

 

Sirolimus (INN/USAN), also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. It prevents activation of T cells and B cells by inhibiting their response to interleukin-2 (IL-2). Sirolimus is also used as a coronary stent coating. Sirolimus works, in part, by eliminating old and abnormal white blood cells.[citation needed] Sirolimus is effective in mice with autoimmunity and in children with a rare condition called autoimmune lymphoproliferative syndrome (ALPS).

sirolimus

macrolide, sirolimus was discovered by Brazilian researchers as a product of the bacterium Streptomyces hygroscopicus in a soil sample fromEaster Island[1] — an island also known as Rapa Nui.[2] It was approved by the FDA in September 1999 and is marketed under the trade nameRapamune by Pfizer (formerly by Wyeth).

Sirolimus was originally developed as an antifungal agent. However, this use was abandoned when it was discovered to have potent immunosuppressive and antiproliferative properties. It has since been shown to prolong the life of mice and might also be useful in the treatment of certain cancers.

Unlike the similarly named tacrolimus, sirolimus is not a calcineurin inhibitor, but it has a similar suppressive effect on the immune system. Sirolimus inhibits the response tointerleukin-2 (IL-2), and thereby blocks activation of T and B cells. In contrast, tacrolimus inhibits the secretion of IL-2.

The mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12(FKBP12) in a manner similar to tacrolimus. Unlike the tacrolimus-FKBP12 complex which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits themammalian target of rapamycin (mTOR, rapamycin being an older name for sirolimus) pathway by directly binding the mTOR Complex1 (mTORC1).

mTOR has also been called FRAP (FKBP-rapamycin associated protein), RAFT (rapamycin and FKBP target), RAPT1, or SEP. The earlier names FRAP and RAFT were coined to reflect the fact that sirolimus must bind FKBP12 first, and only the FKBP12-sirolimus complex can bind mTOR. However, mTOR is now the widely accepted name, since Tor was first discovered via genetic and molecular studies of sirolimus-resistant mutants of Saccharomyces cerevisiae that identified FKBP12, Tor1, and Tor2 as the targets of sirolimus and provided robust support that the FKBP12-sirolimus complex binds to and inhibits Tor1 and Tor2.

rapamycin

Unlike the similarly named tacrolimus, sirolimus is not a calcineurin inhibitor, but it has a similar suppressive effect on the immune system. Sirolimus inhibits the response to interleukin-2 (IL-2), and thereby blocks activation of T and B cells. In contrast, tacrolimus inhibits the secretion of IL-2.

The mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12) in a manner similar to tacrolimus. Unlike the tacrolimus-FKBP12 complex which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the mammalian target of rapamycin(mTOR, rapamycin being an older name for sirolimus) pathway by directly binding the mTOR Complex1 (mTORC1).

mTOR has also been called FRAP (FKBP-rapamycin associated protein), RAFT (rapamycin and FKBP target), RAPT1, or SEP. The earlier names FRAP and RAFT were coined to reflect the fact that sirolimus must bind FKBP12 first, and only the FKBP12-sirolimus complex can bind mTOR. However, mTOR is now the widely accepted name, since Tor was first discovered via genetic and molecular studies of sirolimus-resistant mutants of Saccharomyces cerevisiae that identified FKBP12, Tor1, and Tor2 as the targets of sirolimus and provided robust support that the FKBP12-sirolimus complex binds to and inhibits Tor1 and Tor2.

SIROLIMUS

 

 

 

 

Rapamycin and its preparation are described in US Patent No. 3,929,992, issued December 30, 1975. Alternatively, rapamycin may be purchased commercially [Rapamune®, Wyeth].

 

Rapamycin (Sirolimus) is a 31-member natural macrocyclic lactone [C51H79N1O13; MWt=914.2] produced by Streptomyces hygroscopicus and found in the 1970s (U.S. Pat. No. 3,929,992; 3,993,749). Rapamycin (structure shown below) was approved by the Food and Drug Administration (FDA) for the prophylaxis of renal transplant rejection in 1999.

 

Figure US08088789-20120103-C00001

 

Rapamycin resembles tacrolimus (binds to the same intracellular binding protein or immunophilin known as FKBP-12) but differs in its mechanism of action. Whereas tacrolimus and cyclosporine inhibit T-cell activation by blocking lymphokine (e.g., IL2) gene transcription, sirolimus inhibits T-cell activation and T lymphocyte proliferation by binding to mammalian target of rapamycin (mTOR). Rapamycin can act in synergy with cyclosporine or tacrolimus in suppressing the immune system.

Rapamycin is also useful in preventing or treating systemic lupus erythematosus [U.S. Pat. No. 5,078,999], pulmonary inflammation [U.S. Pat. No. 5,080,899], insulin dependent diabetes mellitus [U.S. Pat. No. 5,321,009], skin disorders, such as psoriasis [U.S. Pat. No. 5,286,730], bowel disorders [U.S. Pat. No. 5,286,731], smooth muscle cell proliferation and intimal thickening following vascular injury [U.S. Pat. Nos. 5,288,711 and 5,516,781], adult T-cell leukemia/lymphoma [European Patent Application 525,960 A1], ocular inflammation [U.S. Pat. No. 5,387,589], malignant carcinomas [U.S. Pat. No. 5,206,018], cardiac inflammatory disease [U.S. Pat. No. 5,496,832], anemia [U.S. Pat. No. 5,561,138] and increase neurite outgrowth [Parker, E. M. et al, Neuropharmacology 39, 1913-1919, 2000].

Although rapamycin can be used to treat various disease conditions, the utility of the compound as a pharmaceutical drug has been limited by its very low and variable bioavailability and its high immunosuppressive potency and potential high toxicity. Also, rapamycin is only very slightly soluble in water. To overcome these problems, prodrugs and analogues of the compound have been synthesized. Water soluble prodrugs prepared by derivatizing rapamycin positions 31 and 42 (formerly positions 28 and 40) of the rapamycin structure to form glycinate, propionate, and pyrrolidino butyrate prodrugs have been described (U.S. Pat. No. 4,650,803). Some of the analogues of rapamycin described in the art include monoacyl and diacyl analogues (U.S. Pat. No. 4,316,885), acetal analogues (U.S. Pat. No. 5,151,413), silyl ethers (U.S. Pat. No. 5,120,842), hydroxyesters (U.S. Pat. No. 5,362,718), as well as alkyl, aryl, alkenyl, and alkynyl analogues (U.S. Pat. Nos. 5,665,772; 5,258,389; 6,384,046; WO 97/35575).

 

 

………………………………………….

Synthesis

http://www.google.co.in/patents/US3929992

PREPARATION

CUT PASTE FROM TEXT

In one embodiment of this invention rapamycin is prepared in the followingmanner: 4

A suitable fermenter is charged with production meis reached in the fermentation mixture after 2-8 days,

usually after about 5 days, as determined by the cup plate method and Candida albicans as the test organism. The mycelium is harvested by filtration with diatomaceous earth. Rapamycin is then extracted from the mycelium with a water-miscible solvent, for example a lower alkanol, preferably methanol or ethanol. The latter extract is then concentrated, preferably under reduced pressure, and the resulting aqueous phase is extracted with a water-immiscible solvent. A preferred water-immiscible solvent for this purpose is methylene dichloride although chloroform, carbon tetrachloride, benzene, n-butanol and the like may also be used. The latter extract is concentrated, preferably under reduced pressure, to afford the crude product as an oil.

The product may be purified further by a variety of methods. Among the preferred methods of purification is to dissolve the crude product in a substantially nonpolar, first solvent, for example petroleum ether or hexane, and to treat the resulting solution with a suit able absorbent, for example charcoal or silica gel, so that the antibiotic becomes absorbed on the absorbant. The absorbant is then separated and washed or eluted with a second solvent more polar than the first solvent, for example ethyl acetate, methylene dichloride, or a mixture of methylene dichloride and ether (preferred). Thereafter, concentration of the wash solution or eluate affords substantially pure rapamycin. Further purification is obtained by partial precipitation with a nonpolar solvent, for example, petroleum ether, hexane, pentane and the like, from a solution of the rapamycin in a more polar solvent, for example, ether, ethyl acetate, benzene and the like. Still-further purification is obtained by column chromatography, preferably employing silica gel, and by crystallization of the rapamycin from ether.

In another preferred embodiment of this invention a first stage inoculum of S treptomyces hygroscopicus NRRL 5491 is prepared in small batches in a medium containing soybean flour, glucose, ammonium sulfate, and calcium carbonate incubated at about 25C at pH 7.l-7.3 for 24 hrs. with agitation, preferably on a gyrotary shaker. The growth thus obtained is used to inoculate a number of somewhat larger batches of the same medium as described above which are incubated at about 25C and pH 7.1-7.3 for 18 hrs. with agitation, preferably on a reciprocating’shaker, to obtain a sec- “ond stagc inoculum which is used to inoculate the production stage fermenters.

6 5.86′.2.-The fermenters are inoculated with the second stage inoculum described above and incubated at about 25C with’ agitationand aeration while controlling and ‘mai’ntaining the mixture at approximately pH 6.0 by

addition offa base, for example, sodium hydroxide, potassium hydroxide or preferably ammonium hydroxide, as required from time to time. Addition of a source -of assimilable carbon, preferably glucose, is started when theconcentrationof the latter in the broth has dropped to about 0.5% wt/vol, normally about 48 hrs after. the start of fermentation, and is maintained until the end ofthe particular run. In this manner a fermentation broth containing about 60 ug/ml of rapamycin as determined by the assay method described above is obtained in 45 days, when fermentation is stopped.

‘ Filtration of the’mycelium, mixing the latter with a watef-miscible ‘lower’ alkanol, preferably methanol, followed by extraction with a halogenated aliphatic hydrocarbon, preferably trichloroethane, and evaporation of the solvents yields a first oily residue. This first oily residue is dissolved in a lower aliphatic ketone, preferably acetone, filtered from insoluble impurities, the filtrate evaporated to yield a second oily residue which is extractedjwith a water-miscible lower alkanol,

preferably methanol, and the latter extract is evaporated to yield crude rapamycin as a third oily residue. This third oily residue is dissolved in a mixture of a lower aliphatic ketone and a lower aliphatic hydrocarbon, preferably acetone-hexane, an absorbent such as charcoal or preferably silica gel is added to adsorb the rapamycin, the latter is eluted from the adsorbate with a similar but more polar solvent mixture, for example a mixture as above but containing a higher proportion of the aliphatic ketone, the eluates are evaporated and the residue is crystallized from diethyl ether, to yield pure crystalline rapamycin. In this manner a total of 45-5 8% of the rapamycin initially present in the fermentation mixture is recovered as pure crystalline rapamycin.

CHARACTERIZATION solvent systems; for example, ether-hexane 40:60 (Rf 0.42), ‘isopropyl alcoholvbenzene 15:85 (Rf= 0.5) and ethanol-benzene 20:80 (Rf f 0.43);

d. rapamycin obtained from four successive fermentation batchesgave the following values on repeated The production stage fermenters are equipped with 7 devices for controlling and maintaining pH at a predetermined level and for continuous metered addition of elemental analyses:

AVER- e. rapamycin exhibits the following characteristic absorption maxima in its ultraviolet absorption spectrum ethanol):

f. the infrared absorption spectrum of rapamycin in chloroform is reproduced in FIG. 1 and shows characteristic absorption bands at 3560, 3430, 1730, 1705 and 1630-1610 cm;

Further infrared absorption bands are characterized by the following data given in reciprocal centimeters with (s) denoting a strong, (m) denoting a medium, and (w) denoting a weak intensity band. This classification is arbitrarily selected in such a manner that a band is denoted as strong (s) if its peak absorption is more than two-thirds of the background in the same region; medium (m) if its peak is between one-third and twothirds of the background in the same region; and weak (w) if its peak is less than one-third of the background in the same region.

2990 cm (m) 1158 cm” (m) 2955 cm (s) 1129 cm (s) 2919 cm (s) 1080 cm (s) 2858 cm (s) 1060 cm (s) 2815 cm (m) 1040 cm (m) 1440 cm (s) 1020 crn’ (m) 1365 cm (m) 978 cm” (s) 1316 cm (in) 905 cm (m) 1272 cm (m) 888 cm” (w) 1178 cm (s) 866 cm- (w) g. the nuclear magnetic resonance spectrum of rapamycinin deuterochloroform is reproduced in FIG. 2; SEE PATENT

CLAIMS

l. Rapamycin, an antibiotic which a. is a colourless, crystalline compound with a melting point of 183 to l8SC, after recrystallization from ether;

b. is soluble in ether, chloroform, acetone, methanol and dimethylformamide, very sparingly soluble in hexane and petroleum ether and substantially insoluble in water;

c. shows a uniform spot on thin layer plates of silica gel”,

d. has a characteristic elemental analysis of about C,

e. exhibits the following characteristic absorption maxima in its ultraviolet absorption spectrum (95% ff has ‘a characteristic infrared absorption spectrum shown in accompanying FIG. 1; SEE PATENT

……………………………………………..

 

Rapamycin synthetic studies. 1. Construction of the C(27)-C(42) subunit. Tetrahedron Lett 1994, 35, 28, 4907

 

 

A partial synthesis of rapamycin has been reported: The condensation of sulfone (I) with epoxide (II) by means of butyllithium followed by desulfonation with Na/Hg gives the partially protected diol (III), which is treated with methanesulfonyl chloride and NaH to afford the epoxide (IV). Ring opening of epoxide (IV) with LiI and BF3.Et2O followed by protection of the resulting alcohol with PMBOC(NH)CCl3 yields the primary iodo compound (V). The condensation of (V) with the fully protected dihydroxyaldehyde (VI) (see later) by means of butyllithium in THF/HMPT gives the fully protected trihydroxyketone (VII), which is hydrolyzed with camphorsulfonic acid (CSA) to the corresponding gemdiol and reprotected with pivaloyl chloride (the primary alcohol) and tert-butyldimethylsilyl trifluoromethanesulfonate (the secondary alcohol), yielding a new fully protected trihydroxyketone (VIII). Elimination of the pivaloyl group with DIBAL and the dithiane group with MeI/CaCO3 affords the hydroxyketone (IX), which is finally oxidized with oxalyl chloride to the ketoaldehyde (X), the C(27)-C(42) fragment [the C(12)-C(15) fragment with the C(12)-substituent based on the IUPAC nomenclature recommendations]. The fully protected dihydroxyaldehyde (VI) is obtained as follows: The reaction of methyl 3-hydroxy-2(R)-methylpropionate (XI) with BPSCl followed by reduction with LiBH4 to the corresponding alcohol and oxidation with oxalyl chloride gives the aldehyde (XII), which is protected with propane-1,3-dithiol and BF3.Et2O to afford the dithiane compound (XIII). Elimination of the silyl group with TBAF followed by esterification with tosyl chloride, reaction with NaI and, finally, with sodium phenylsulfinate gives the sulfone (XIV), which is condensed with the partially protected dihydroxyaldehyde (XV), oxidized with oxalyl chloride and desulfonated with Al/Hg to afford the dithianyl ketone (XVI). The reaction of (XVI) with lithium hexamethyldisilylazane gives the corresponding enolate, which is treated with dimethyllithium cuprate to yield the fully protected unsaturated dihydroxyaldehyde (VI).

 

……………………………………………

http://www.google.com/patents/US8088789

JUT HAVE A LOOK

……………………………

The Ley Synthesis of Rapamycin

Rapamycin (3) is used clinically as an immunosuppressive agent. The synthesis of 3 (Angew. Chem. Int. Ed. 200746, 591. DOI: 10.1002/anie.200604053) by Steven V. Ley of the University of Cambridge was based on the assembly and subsequent coupling of the iododiene 1 and the stannyl alkene 2.

The lactone of 1 was prepared by Fe-mediated cyclocarbonylation of the alkenyl epoxide 5, following the protocol developed in the Ley group.

The cyclohexane of 2 was constructed by SnCl4-mediated cyclization of the allyl stannane 9, again employing a procedure developed in the Ley group. Hydroboration delivered the aldehyde 11, which was crotylated with 12, following the H. C. Brown method. The alcohol so produced (not illustrated) was used to direct the diastereoselectivity of epoxidation, then removed, to give 13. Coupling with 14 then led to 2.

Combination of 1 with 2 led to 15, which was condensed with catechol to give the macrocycle 16. Exposure of 16 to base effected Dieckmann cyclization, to deliver the ring-contracted macrolactone 17, which was carried on to (-)-rapamycin (3).

 

……………………………….

Total Synthesis of Rapamycin

Angewandte Chemie International Edition

Volume 46, Issue 4, pages 591–597, January 15, 2007

Thumbnail image of graphical abstract

PREVIEW THIS ARTICLE WITH READCUBE

Readcube-logo

http://www.readcube.com/articles/10.1002%2Fanie.200604053?r3_referer=wol

 

……………………..

rapamycin_1.jpg

Ley, Maddess, Tackett, Watanabe, Brennan, Spilling, Scott and Osborn. ACIEE2006EarlyView. DOI:10.1002/anie.200604053.

It’s been in the works for quite a while, but Steve Ley’s synthesis of Rapamycin has just been published. This complex beast has a multitude of biological activities, including an interesting immunosuppressive profile, resulting in clinical usage following organ transplantation. So, unsurprisingly, it’s been the target of many projects, with complete total syntheses published by SmithDanishefskySchreiber and KCN.

So what makes this one different? Well, it does have one of the most interesting macrocyclisations I’ve seen since Jamison’s paper, and a very nice demonstration of the BDA-aldol methodology. The overall strategy is also impressive, so on with the retro:

rapamycin_2.jpg
First stop is the BDA-aldol; this type of chemistry is interesting, because the protecting group for the diol is also the stereo-directing group. The stereochemistry for this comes from a glycolic acid, and has been usedin this manner by the group before. The result is as impressive as ever, with a high yield, and presumably a very high d.r. (no mention of actual numbers).

rapamycin_3.jpg

The rest of the fragment synthesis was completed in a succinct and competent manner, but using relatively well known chemistry. However, I was especially impressed with the macrocyclisation I mentioned:

rapamycin_4.jpg

Tethering the free ends of the linear precursor with a simple etherification/esterification onto catechol gave then a macrocycle holding the desired reaction centres together. Treatment of this with base then induces a Dieckmann-condensation type cyclisation to deliver the desired macrocycle. Of course, at this stage, only a few more steps were required to complete the molecule, and end an era of the Wiffen Lab.

………………………………

Drugs Fut 1999, 24(1): 22

DOI: 10.1358/dof.1999.024.01.474036

 

 

REFERENCES

  1.  Vézina C, Kudelski A, Sehgal SN (October 1975). “Rapamycin (AY-22,989), a new antifungal antibiotic”J. Antibiot. 28 (10): 721–6. doi:10.7164/antibiotics.28.721PMID 1102508.
  2. Pritchard DI (2005). “Sourcing a chemical succession for cyclosporin from parasites and human pathogens”. Drug Discovery Today 10 (10): 688–691. doi:10.1016/S1359-6446(05)03395-7PMID 15896681.

 

3. Creating diverse target-binding surfaces on FKBP12: synthesis and evaluation of a rapamycin analogue library.

Wu X, Wang L, Han Y, Regan N, Li PK, Villalona MA, Hu X, Briesewitz R, Pei D.

ACS Comb Sci. 2011 Sep 12;13(5):486-95. doi: 10.1021/co200057n. Epub 2011 Jul 28.

4. Mammalian target of rapamycin: discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growth.

Gibbons JJ, Abraham RT, Yu K.

Semin Oncol. 2009 Dec;36 Suppl 3:S3-S17. doi: 10.1053/j.seminoncol.2009.10.011. Review.

5. Hybrid inhibitors of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR): design, synthesis, and superior antitumor activity of novel wortmannin-rapamycin conjugates.

Ayral-Kaloustian S, Gu J, Lucas J, Cinque M, Gaydos C, Zask A, Chaudhary I, Wang J, Di L, Young M, Ruppen M, Mansour TS, Gibbons JJ, Yu K.

J Med Chem. 2010 Jan 14;53(1):452-9. doi: 10.1021/jm901427g.

6. Fluorescent probes to characterise FK506-binding proteins.

Kozany C, März A, Kress C, Hausch F.

Chembiochem. 2009 May 25;10(8):1402-10. doi: 10.1002/cbic.200800806.

 

7. Recent advances in the chemistry, biosynthesis and pharmacology of rapamycin analogs.

Graziani EI.

Nat Prod Rep. 2009 May;26(5):602-9. doi: 10.1039/b804602f. Epub 2009 Mar 5. Review.

Total synthesis of rapamycin.

Ley SV, Tackett MN, Maddess ML, Anderson JC, Brennan PE, Cappi MW, Heer JP, Helgen C, Kori M, Kouklovsky C, Marsden SP, Norman J, Osborn DP, Palomero MA, Pavey JB, Pinel C, Robinson LA, Schnaubelt J, Scott JS, Spilling CD, Watanabe H, Wesson KE, Willis MC.

Chemistry. 2009;15(12):2874-914. doi: 10.1002/chem.200801656.

9  Highly diastereoselective desymmetrisation of cyclic meso-anhydrides and derivatisation for use in natural product synthesis.

Evans AC, Longbottom DA, Matsuoka M, Davies JE, Turner R, Franckevicius V, Ley SV.

Org Biomol Chem. 2009 Feb 21;7(4):747-60. doi: 10.1039/b813494d. Epub 2009 Jan 6.

10  Total synthesis studies on macrocyclic pipecolic acid natural products: FK506, the antascomicins and rapamycin.

Maddess ML, Tackett MN, Ley SV.

Prog Drug Res. 2008;66:13, 15-186. Review.

11 Determination of sirolimus in rabbit arteries using liquid chromatography separation and tandem mass spectrometric detection.

Zhang J, Rodila R, Watson P, Ji Q, El-Shourbagy TA.

Biomed Chromatogr. 2007 Oct;21(10):1036-44.

12  Saccharomyces cerevisiae FKBP12 binds Arabidopsis thaliana TOR and its expression in plants leads to rapamycin susceptibility.

Sormani R, Yao L, Menand B, Ennar N, Lecampion C, Meyer C, Robaglia C.

BMC Plant Biol. 2007 Jun 1;7:26.

13 Total synthesis of rapamycin.

Maddess ML, Tackett MN, Watanabe H, Brennan PE, Spilling CD, Scott JS, Osborn DP, Ley SV.

Angew Chem Int Ed Engl. 2007;46(4):591-7. No abstract available.

15 lipase-catalyzed regioselective esterification of rapamycin: synthesis of temsirolimus (CCI-779).

Gu J, Ruppen ME, Cai P.

Org Lett. 2005 Sep 1;7(18):3945-8.

16 CCI-779 Wyeth.

Elit L.

Curr Opin Investig Drugs. 2002 Aug;3(8):1249-53. Review.

 

17 Everolimus. Novartis.

Dumont FJ.

Curr Opin Investig Drugs. 2001 Sep;2(9):1220-34. Review.

 

18 Kuo et al (1992) Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature 358 70. PMID:1614535.

 

19 Huang et al (2003) Rapamycins: mechanism of action and cellular resistance. Cancer Biol.Ther. 2 221. PMID:12878853.

 

20 Kobayashi et al (2007) Rapamycin, a specific inhibitor of the mammalian target of rapamycin, suppresses lymphangiogenesis and lymphatic metastasis. Cancer Sci. 98 726. PMID: 17425689.

 

21 Fleming et al (2011) Chemical modulators of autophagy as biological probes and potential therapeutics. 7 9. PMID:21164513.

 

22 J Am Chem Soc1993,115,(10):4419

 

23 Tetrahedron Lett1994,35,(28):4911

24 Chemistry (Weinheim)1995,1,(5):318

 

24

Figure imgf000004_0001SIROLIMUS

 

FEMALE FERTILITY

http://amcrasto.theeurekamoments.com/2013/02/11/immunosuppressant-drug-rapamycin-helps-preserving-female-fertility/

 

PATENTS

Canada 2293793 APPROVED2006-07-11 EXP    2018-06-11
Canada 2103571                 2003-04-29           2012-02-21
United States 5989591                 1998-09-11           2018-09-11
United States 5212155                 1993-05-18           2010-05-18

 

 

WO1998054308A2 * May 28, 1998 Dec 3, 1998 Biotica Tech Ltd Polyketides and their synthesis and use
EP0589703A1 * Sep 23, 1993 Mar 30, 1994 American Home Products Corporation Proline derivative of rapamycin, production and application thereof
US20010039338 * Jun 7, 2001 Nov 8, 2001 American Home Products Corporation Regioselective synthesis of rapamycin derivatives

 

WO2007067560A2 * Dec 6, 2006 Jun 14, 2007 Clifford William Coughlin Scalable process for the preparation of a rapamycin 42-ester from a rapamycin 42-ester boronate
WO2012131019A1 Mar 30, 2012 Oct 4, 2012 Sandoz Ag Regioselective acylation of rapamycin at the c-42 position
US7622578 Dec 6, 2006 Nov 24, 2009 Wyeth Scalable process for the preparation of a rapamycin 42-ester from a rapamycin 42-ester boronate

 

US3929992 Apr 12, 1974 Dec 30, 1975 Ayerst Mckenna & Harrison Rapamycin and process of preparation
US5646160 May 26, 1995 Jul 8, 1997 American Home Products Corporation Method of treating hyperproliferative vascular disease with rapamycin and mycophenolic acid
US5665772 Sep 24, 1993 Sep 9, 1997 Sandoz Ltd. O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants
US5728710 Jul 16, 1993 Mar 17, 1998 Smithkline Beecham Corporation Rapamycin derivatives
US5957975 Dec 15, 1997 Sep 28, 1999 The Centre National De La Recherche Scientifique Stent having a programmed pattern of in vivo degradation
US5985890 Jun 5, 1996 Nov 16, 1999 Novartis Ag Rapamycin derivatives
US6001998 Oct 13, 1995 Dec 14, 1999 Pfizer Inc Macrocyclic lactone compounds and their production process
US6015815 Sep 24, 1998 Jan 18, 2000 Abbott Laboratories Tetrazole-containing rapamycin analogs with shortened half-lives
US6187568 Aug 20, 1999 Feb 13, 2001 Pfizer Inc Macrocyclic lactone compounds and their production process
US6273913 Apr 16, 1998 Aug 14, 2001 Cordis Corporation Modified stent useful for delivery of drugs along stent strut
US6585764 Jun 4, 2001 Jul 1, 2003 Cordis Corporation Stent with therapeutically active dosage of rapamycin coated thereon
US6641611 Nov 26, 2001 Nov 4, 2003 Swaminathan Jayaraman Therapeutic coating for an intravascular implant
US6805703 Sep 18, 2001 Oct 19, 2004 Scimed Life Systems, Inc. Protective membrane for reconfiguring a workpiece
US7025734 Sep 28, 2001 Apr 11, 2006 Advanced Cardiovascular Systmes, Inc. Guidewire with chemical sensing capabilities
US7056942 Jan 16, 2004 Jun 6, 2006 Teva Pharmaceutical Industries Ltd. Carvedilol
US7820812 * Jul 23, 2007 Oct 26, 2010 Abbott Laboratories Methods of manufacturing crystalline forms of rapamycin analogs
US20010027340 Jun 4, 2001 Oct 4, 2001 Carol Wright Stent with therapeutically active dosage of rapamycin coated thereon
US20010029351 May 7, 2001 Oct 11, 2001 Robert Falotico Drug combinations and delivery devices for the prevention and treatment of vascular disease
US20020005206 May 7, 2001 Jan 17, 2002 Robert Falotico Antiproliferative drug and delivery device
US20020007213 May 7, 2001 Jan 17, 2002 Robert Falotico Drug/drug delivery systems for the prevention and treatment of vascular disease
US20020082680 Sep 7, 2001 Jun 27, 2002 Shanley John F. Expandable medical device for delivery of beneficial agent
US20020123505 Sep 10, 2001 Sep 5, 2002 Mollison Karl W. Medical devices containing rapamycin analogs
US20030129215 Sep 6, 2002 Jul 10, 2003 T-Ram, Inc. Medical devices containing rapamycin analogs
US20040072857 Jul 2, 2003 Apr 15, 2004 Jacob Waugh Polymerized and modified rapamycins and their use in coating medical prostheses
US20050033417 Jul 1, 2004 Feb 10, 2005 John Borges Coating for controlled release of a therapeutic agent
US20050101624 Nov 12, 2003 May 12, 2005 Betts Ronald E. 42-O-alkoxyalkyl rapamycin derivatives and compositions comprising same
US20050152842 Dec 22, 2004 Jul 14, 2005 Chun Li Poly (L-glutamic acid) paramagnetic material complex and use as a biodegradable MRI contrast agent
US20050175660 Oct 29, 2004 Aug 11, 2005 Mollison Karl W. Medical devices containing rapamycin analogs
US20050208095 Nov 22, 2004 Sep 22, 2005 Angiotech International Ag Polymer compositions and methods for their use
US20050209244 Feb 27, 2003 Sep 22, 2005 Prescott Margaret F N{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine coated stents
US20050239178 Apr 25, 2005 Oct 27, 2005 Wyeth Labeling of rapamycin using rapamycin-specific methylases
US20060094744 Sep 28, 2005 May 4, 2006 Maryanoff Cynthia A Pharmaceutical dosage forms of stable amorphous rapamycin like compounds
US20060229711 Apr 4, 2006 Oct 12, 2006 Elixir Medical Corporation Degradable implantable medical devices
US20070015697 Nov 1, 2005 Jan 18, 2007 Peyman Gholam A Enhanced ocular neuroprotection and neurostimulation
US20070059336 Feb 27, 2006 Mar 15, 2007 Allergan, Inc. Anti-angiogenic sustained release intraocular implants and related methods
US20070207186 Mar 3, 2007 Sep 6, 2007 Scanlon John J Tear and abrasion resistant expanded material and reinforcement
US20080086198 May 24, 2007 Apr 10, 2008 Gary Owens Nanoporous stents with enhanced cellular adhesion and reduced neointimal formation
EP1236478A1 Feb 27, 2002 Sep 4, 2002 Medtronic Ave, Inc. Peroxisome proliferator-activated receptor gamma ligand eluting medical device
EP1588727A1 Apr 20, 2005 Oct 26, 2005 Cordis Corporation Drug/drug delivery systems for the prevention and treatment of vascular disease
WO1993016189A1 Feb 11, 1993 Aug 19, 1993 Pfizer Novel macrocyclic lactones and a productive strain thereof
WO1994009010A1 Sep 24, 1993 Apr 28, 1994 Sandoz Ag O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants
WO1996041807A1 Jun 5, 1996 Dec 27, 1996 Sylvain Cottens Rapamycin derivatives
WO1998007415A2 Aug 18, 1997 Feb 26, 1998 Ciba Geigy Ag Methods for prevention of cellular proliferation and restenosis
WO2001087263A2 May 14, 2001 Nov 22, 2001 Cordis Corp Delivery systems for treatment of vascular disease
WO2001087342A2 May 14, 2001 Nov 22, 2001 Cordis Corp Delivery devices for treatment of vascular disease
WO2001087372A1 Apr 25, 2001 Nov 22, 2001 Cordis Corp Drug combinations useful for prevention of restenosis
WO2001087373A1 May 14, 2001 Nov 22, 2001 Cordis Corp Delivery devices for treatment of vascular disease
WO2001087374A1 May 14, 2001 Nov 22, 2001 Cordis Corp Delivery systems for treatment of vascular disease
WO2001087375A1 May 14, 2001 Nov 22, 2001 Cordis Corp Delivery devices for treatment of vascular disease
WO2001087376A1 May 14, 2001 Nov 22, 2001 Cordis Corp Drug/drug delivery systems for the prevention and treatment of vascular disease
WO2002056790A2 Dec 18, 2001 Jul 25, 2002 Avantec Vascular Corp Delivery of therapeutic capable agents
WO2002065947A2 Feb 18, 2002 Aug 29, 2002 Jomed Gmbh Implants with fk506 for prophylaxis and treatment of restonoses
WO2003064383A2 Feb 3, 2003 Aug 7, 2003 Ariad Gene Therapeutics Inc Phosphorus-containing compounds & uses thereof
WO2006116716A2 Apr 27, 2006 Nov 2, 2006 William A Dunn Materials and methods for enhanced degradation of mutant proteins associated with human disease

A plaque, written in Brazilian Portuguese, commemorating the discovery of sirolimus on Easter Island, near Rano Kau

 

mTOR inhibitor

temsirolimus (CCI-779), everolimus (RAD001), deforolimus (AP23573), AP21967, biolimus, AP23102, zotarolimus (ABT 578), sirolimus (Rapamune), and tacrolimus (Prograf).

Share
Follow

Get every new post on this blog delivered to your Inbox.

Join other followers: