DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India, in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA as ADVISOR earlier GLENMARK LS Research centre as consultant,Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now sSanofi, Searle India ltd, now Rpg lifesciences, etc. he is now helping millions, has million hits on google on all organic chemistry websites. His New Drug Approvals, Green Chemistry International, Eurekamoments in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide . He gas good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, polymorphism etc He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has one lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463, amcrasto@gmail.com

Structural evolution of carbon in an Fe@C catalyst during the Fischer–Tropsch synthesis reaction

ANTHONY CRASTO, organic chemistry, SYNTHESIS Comments Off

Feb 012019

Structural evolution of carbon in an Fe@C catalyst during the Fischer–Tropsch synthesis reaction

Shuai Lyu,^a^b Chengchao Liu,^b Guanghui Wang,*^a Yuhua Zhang,^b Jinlin Li^b and Li Wang*^b

Author affiliations

*Corresponding authors

^aHubei Key Laboratory of Coal Conversion and New Carbon Material, School of Chemical Engineering and Technology, Wuhan University of Science and Technology, Wuhan 430081, China
E-mail: wghwang@263.net

^bKey Laboratory of Catalysis and Materials Science of the State Ethnic Affairs Commission & Ministry of Education, South-Central University for Nationalities, Wuhan 430074, China
E-mail: li.wang@mail.scuec.edu.cn

Abstract

A pseudo-in situ research method was applied to provide insight into the structural evolution of carbon in an Fe@C catalyst at different stages of the Fischer–Tropsch reaction. Five typical stages of the catalyst were selected for in-depth structural investigation; these were: the fresh catalyst, reduced catalyst, and catalyst in the stable conversion period, in an increased-conversion period and at the inactivation stage. The results indicated that the integral structure of Fe@C constantly changed in the Fischer–Tropsch reaction. Iron carbide transformed from the Fe phase that was easily oxidized under high temperature Fischer–Tropsch conditions, and the carbon framework was completely destroyed in the reaction process, leading to a drastic decrease in the specific surface area of the material. This destruction could have two opposing effects: on the one hand, the loss of carbon could re-expose the active sites that have been covered by carbon at a reaction temperature of 320 °C and favor the reaction; on the other hand, the deposition of carbon could block the active sites and lead to inactivation when the reaction temperature is over 340 °C.

https://pubs.rsc.org/en/Content/ArticleLanding/2019/CY/C8CY02420K?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2Fcy+%28RSC+-+Catalysis+Science+%26+Technology+latest+articles%29#!divAbstract

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Telescoped Sequence of Exothermic and Endothermic Reactions in Multistep Flow Synthesis

FLOW CHEMISTRY, flow synthesis Comments Off

Jan 312019

A multistep sequential flow synthesis of isopropyl phenol is demonstrated, involving 4-step exothermic, endothermic, and temperature sensitive reactions such as nitration, reduction, diazotization, and high temperature hydrolysis. Nitration of cumene with fuming nitric acid produces 2- and 4-nitrocumene which are converted into respective cumidines by the hydrogenation using Pd/Ni catalyst in H-cube with gravity separation. Hydrolysis of in situ generated diazonium salts in the boiling acidic conditions is carried out using integration of flow and microwave-assisted synthesis. 58% of 4-isopropyl phenol was obtained. The sequential flow synthesis can be applied to synthesize other organic compounds involving this specific sequence of reactions.

Telescoped Sequence of Exothermic and Endothermic Reactions in Multistep Flow Synthesis

Yachita Sharma, Arun V. Nikam, and Amol A. Kulkarni*

Chemical Engineering & Process Development Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00008

Yachita Sharma

*Phone: +91-20-25902153, E-mail: aa.kulkarni@ncl.res.in.

Amol A. Kulkarni

Dr.Amol A. Kulkarni
Chemical Engineering & Process Development
CSIR-National Chemical Laboratory

Dr. Amol A. Kulkarni is a Scientist in the Chemical Engineering Division at the National Chemical Laboratory. He did his B. Chem. Eng. (1998), M. Chem. Eng (2000) and Ph.D. in chemical engineering (2003) all from the University Dept. of Chem. Technology (UDCT, Mumbai). In 2004 he worked at the Max Planck Institute-Magdeburg (Germany) as a Alexander von Humboldt Research Fellow. At NCL he is driving a research program on the design of microreactors and exploring their applications for continuous syntheses including of nanoparticles. He has been awarded with the Max-Planck-Visiting Fellowship from the Max-Planck-Society, Munich for 2008-2011. His research areas include: (i) design and applications of microreactors, (ii) design of multiphase reactors, (iii) experimental and computational fluid dynamics, and (iv) nonlinear dynamics of coupled systems. He is an active member of Initiative for Research and Innovation in Science (IRIS) supported by Intel’s Education Initiative to organize National Science Fair and popularize science in India.

Yachita Sharma

CSIR – National Chemical Laboratory, Pune

Location Pune, India

Department, Chemical Engineering and Process Development Division (NCL)

Yachita Sharma is a PhD student at CSIR-National Chemical Laboratory, Pune (India). She received her MSc in Applied Organic Chemistry in 2010. Her work focuses on exploring the continuous flow synthesis involving exothermic reactions and their integration.

Arun Nikam

CSIR – National Chemical Laboratory, Pune

Location, Pune, India

Department, Chemical Engineering and Process Development Division (NCL)

Email: arun11nikam@gmail.com

Arun was born and raised in Koregaon, Maharashtra, India. He completed his bachelors and masters in chemical sciences from Shivaji Unversity, Kolhapur, India. Currently, He is pursuing his Ph. D. under the supervision of Dr. Amol A. Kulkarni and Dr. B. L. V. Prasad. His work mainly focuses on flow synthesis of nanoparticles, drug formulation, and polymers. He develops new synthesis procedures and translates into flow chemistry to increase productivity with excellent control over the quality of the product. He is also exploring the application of nanoparticles in catalysis, electronics and pharmaceutical fields. He specializes in microwave-assisted continuous flow synthesis of nanomaterial and organic intermediate. Apart from his research, he actively pursues Yoga and spirituality. He also likes to play volleyball and has competed in inter CSIR tournaments.

/////////isopropyl phenol, flow chem,

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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ANTHONY MELVIN CRASTO

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Nickel-catalyzed regioselective C–H oxygenation: new routes for versatile C–O bond formation

spectroscopy, SYNTHESIS Comments Off

Jan 302019

Graphical abstract: Nickel-catalyzed regioselective CâH oxygenation: new routes for versatile CâO bond formation

Nickel-catalyzed regioselective C–H oxygenation: new routes for versatile C–O bond formation

Org. Chem. Front., 2019, Advance Article
DOI: 10.1039/C8QO01274A, Research Article

Ze-lin Li, Kang-kang Sun, Chun Cai
Nickel-catalyzed regioselective C–H oxygenation reactions of chelating arenes using iodobenzene diacetate, alcohols, and benzoic acids respectively as attacking reagents have been developed for the first time.
To cite this article before page numbers are assigned, use the DOI form of citation above.

Abstract

Nickel-catalyzed regioselective C–H oxygenation reactions of chelating arenes using iodobenzene diacetate, alcohols, and benzoic acids respectively as attacking reagents have been developed for the first time. Simplicity of operation, broad range of functional group tolerance, use of cheap transition metal nickel, and avoiding extraneous directing groups are the key features, thus providing an important complement to C–H oxygenation reactions and expanding the field of nickel-catalyzed C–H functionalizations. Explorations of mechanistic details are also described.

Nickel-catalyzed regioselective C–H oxygenation: new routes for versatile C–O bond formation

Ze-lin Li,^a Kang-kang Sun^a and Chun Cai*^a

Author affiliations

*Corresponding authors

^aCollege of Chemical Engineering, Nanjing University of Science & Technology, 200 Xiaolingwei, Nanjing, China
E-mail:c.cai@njust.edu.cn

https://pubs.rsc.org/en/Content/ArticleLanding/2019/QO/C8QO01274A#!divAbstract

2-(pyridin-2-yl)phenyl acetate (2a)

Formula: C13H11NO2 Mass: 213

To a mixture of 2-phenylpyridine (77.5 mg, 0.5 mmol) 1a, Ni(acac)2 (25.7 mg, 0.1 mmol, 20 mol %), ligand MePh2P (20.0 mg, 0.1 mmol, 20 mol %), and PhI(OAc)2 (483.2 mg, 0.75 mmol, 1.5 equiv) in a reaction tube was added solvent (CH3CN=2.0 mL). The reaction mixture was stirred at 115 °C for 24 h in air. Following the general procedure, 2a was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 5:1) as a white solid (80.9 mg, 76%).

1H NMR (500 MHz, Chloroform-d) δ 8.8 – 8.7 (m, 1H), 7.8 – 7.7 (m, 2H), 7.6 (dd, J = 7.9, 1.1 Hz, 1H), 7.5 (td, J = 7.7, 1.7 Hz, 1H), 7.4 (td, J = 7.5, 1.2 Hz, 1H), 7.3 – 7.3 (m, 1H), 7.2 (dd, J = 8.0, 1.2 Hz, 1H), 2.2 (s, 3H).

13C NMR (126 MHz, Chloroform-d) δ 168.4, 154.9, 148.6, 147.1, 135.3, 132.2, 129.8, 128.7, 125.4, 122.6, 122.3, 121.2, 20.0. GC-MS (EI) m/z: 213

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“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

READ

ANTHONY MELVIN CRASTO

https://newdrugapprovals.org/

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A solvent-free catalytic protocol for the Achmatowicz rearrangement

green chemistry, spectroscopy, SYNTHESIS Comments Off

Jan 292019

Graphical abstract: A solvent-free catalytic protocol for the Achmatowicz rearrangement

Abstract

Reported here is the development of an environmentally friendly catalytic (KBr/oxone) and solvent-free protocol for the Achmatowicz rearrangement (AchR). Different from all previous methods is that the use of chromatographic alumina (Al₂O₃) allows AchR to proceed smoothly in the absence of any organic solvent and therefore considerably facilitates the subsequent workup and purification with minimal environmental impacts. Importantly, this protocol allows for scaling up (from milligram to gram), recycling of the Al₂O₃, and integrating with other reactions in a one-pot sequential manner.

A solvent-free catalytic protocol for the

Achmatowicz rearrangement

Guodong Zhao^a and Rongbiao Tong*^a^b

Author affiliations

*Corresponding authors

^aDepartment of Chemistry, The Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, China
E-mail: rtong@ust.hk
Fax: +(852)23581594
Tel: +(852) 23587357

^bHKUST Shenzhen Research Institute, Shenzhen 518057, China

https://pubs.rsc.org/en/Content/ArticleLanding/2019/GC/C8GC03030H?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

1n: colorless oil, 0.33 g, 73% yield for 2 steps.

1H-NMR (400 MHz, DMSO) δ: 7.59–7.58 (m, 1H), 7.45 (s, 2H), 6.40 (dd, J = 3.2, 1.8 Hz, 1H), 6.29 (d, J = 3.2 Hz, 1H), 5.49 (s, 1H), 4.74–4.60 (m, 1H), 4.18–4.07 (m, 2H), 2.09–2.04 (m, 2H).

13C-NMR (100 MHz, DMSO) δ: 157.6, 142.4, 110.7, 106.1, 66.5, 62.8, 35.2. IR (KBr) 3282.9, 2928.7, 1627.4, 1562.5, 1353.8, 1174.6, 1074.0, 999.7, 918.4, 742.8 cm-1 ;

HRMS (CI+ ) (m/z) calcd. for C7H11NO5S [M]+ 221.0352; found 221.0354.

2n (EtOAc/hexane = 3:1):colorless oil (dr 7:3), 46 mg, 97%.

1H-NMR (400 MHz, DMSO) δ: 7.48–7.47 (m, 2H), 7.34–7.02 (m, 2H), 6.12–6.03 (m, 1H), 5.61–5.48 (m, 1H), 4.60 (dd, J = 8.3, 4.1 Hz, 0.7H), 4.28 (ddd, J = 8.8, 4.0, 1.3 Hz, 0.3H), 4.20–4.11 (m, 2H), 2.27–2.20 (m, 1H), 1.97–1.86 (m, 1H).

13C-NMR (100 MHz, DMSO) δ: 196.7, 196.5, 151.9, 148.3, 127.7, 126.0, 90.9, 87.2, 74.6, 70.1, 65.8, 65.8, 30.3, 29.6. IR (KBr) 3370.4, 2987.0, 1689.5, 1364.3, 1268.0, 1178.4, 1023.3, 928.3, 755.1 cm-1 ;

HRMS (CI+ ) (m/z) calcd. for C7H11NO6S [M]+ 237.0302; found 237.0315.

////////////////Achmatowicz rearrangement

Eco-friendly decarboxylative cyclization in water: practical access to the anti-malarial 4-quinolones

spectroscopy, SYNTHESIS Comments Off

Jan 292019

Graphical abstract: Eco-friendly decarboxylative cyclization in water: practical access to the anti-malarial 4-quinolones

Abstract

An environmentally benign decarboxylative cyclization in water has been developed to synthesize 4-quinolones from readily available isatoic anhydrides and 1,3-dicarbonyl compounds. Isatins are also compatible for the reaction to generate 4-quinolones in the presence of TBHP in DMSO. This protocol provides excellent yields under mild conditions for a broad scope of 4-quinolones, and has good functional group tolerance. Only un-harmful carbon dioxide and water are released in this procedure. Moreover, the newly synthesized products have also been selected for anti-malarial examination against the chloroquine drug-sensitive Plasmodium falciparum 3D7 strain. 3u is found to display excellent anti-malarial activity with an IC₅₀ value of 33 nM.

Eco-friendly decarboxylative cyclization in water: practical access to the anti-malarial 4-quinolones

Yue Ma,^a Yongping Zhu,^a Dong Zhang,^a Yuqing Meng,^a Tian Tang,^a Kun Wang,^a Ji Ma,^a Jigang Wang^a and Peng Sun*^a

Author affiliations

*Corresponding authors

^aArtermisinin Research Center and Institute of Chinese Meteria Medica, Academy of Chinese Medical Sciences, Beijing, P. R. China
E-mail:psun@icmm.ac.cn

https://pubs.rsc.org/en/Content/ArticleLanding/2019/GC/C8GC03570A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

ethyl 2-(4-(benzyloxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (3u) White solid, m.p. 288-289 oC;

1H NMR (600 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.72 (ddd, J = 8.4, 7.1, 1.5 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.52 (td, J = 8.5, 1.7 Hz, 1H), 7.43 – 7.35 (m, 4H), 7.29 – 7.21 (m, 4H), 7.10 (td, J = 7.5, 0.5 Hz, 1H), 5.17 (s, 2H), 3.91 (q, J = 7.1 Hz, 2H), 2.00 (s, 1H), 0.83 (t, J = 7.1 Hz, 3H) ppm;

13C NMR (150 MHz, DMSO-d6) δ 174.1, 166.2, 156.2, 148.0, 139.8, 137.2, 132.8, 132.0, 130.5, 129.4, 128.7, 128.2, 127.6, 125.5, 125.2, 124.3, 123.6, 120.9, 118.9, 116.4, 115.8, 113.5, 70.2, 60.2, 14.0 ppm;

HRMS (ESI) calcd for [C25H21NO4+H]+ 400.1471, found 400.1463.

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Photo-organocatalytic synthesis of acetals from aldehydes

organic chemistry, spectroscopy, SYNTHESIS Comments Off

Jan 292019

Graphical abstract: Photo-organocatalytic synthesis of acetals from aldehydes

Abstract

A mild and green photo-organocatalytic protocol for the highly efficient acetalization of aldehydes has been developed. Utilizing thioxanthenone as the photocatalyst and inexpensive household lamps as the light source, a variety of aromatic and aliphatic aldehydes have been converted into acyclic and cyclic acetals in high yields. The reaction mechanism was extensively studied

Photo-organocatalytic synthesis of acetals from aldehydes

Nikolaos F. Nikitas,^a Ierasia Triandafillidi^a and Christoforos G. Kokotos*^a

Author affiliations

*Corresponding authors

^aLaboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece
E-mail:ckokotos@chem.uoa.gr

https://pubs.rsc.org/en/Content/ArticleLanding/2019/GC/C8GC03605E?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

(3,3-Dimethoxypropyl)benzene (2a)6

Colorless oil; 95% yield; 1H NMR (200 MHz, CDCl3) δ: 7.33-7.18 (5H, m, ArH), 4.37 (1H, t, J = 5.8 Hz, OCH), 3.33 (6H, s, 2 x OCH3), 2.68 (2H, t, J = 7.6 Hz, CH2), 1.98- 1.87 (2H, m, CH2); 13C NMR (50 MHz, CDCl3) δ: 141.8, 128.4, 125.9, 103.7, 52.8, 34.0, 30.8; MS (ESI) m/z 181 [M+H]+ .

6. Q. Zhou, T. Jia. X.-X. Li, L. Zhou, C.-J. Li, Y. S. Feng, Synth. Commun., 2018, 48, 1068.

.////////////////

Large scale synthesis of chiral (3Z,5Z)-2,7-dihydro-1H-azepine-derived Hamari ligand for general asymmetric synthesis of tailor-made amino acids.

spectroscopy, SYNTHESIS Comments Off

Jan 292019

(R)-2,2′-bis(bromomethyl)-1,1′-binaphthalene ((R)-17) was prepared in the identical manner and had identical analytical properties to those given here.

¹H NMR (400 MHz, CDCl₃): δ 4.25 (4H, s, 2 × CH₂), 7.07 (2H, dd, J = 8.4, 0.8 Hz, ArH), 7.27 (2H, ddd, J = 8.4, 6.8, 1.2 Hz, ArH), 7.48 (2H, ddd, J = 8.2, 6.8, 1.2 Hz, ArH), 7.74 (2H, d, J = 8.6 Hz, ArH), 7.92 (2H, d, J = 8.2 Hz, ArH), 8.02 (2H, d, J = 8.6 Hz, ArH).

¹³C NMR (100.6 MHz, CDCl₃): δ 32.6 (CH₂), 126.80 (ArCH), 126.82 (ArCH), 126.84 (ArCH), 127.7 (ArCH), 128.0 (ArCH), 129.4 (ArCH), 132.5 (quaternary ArC), 133.3 (quaternary ArC), 134.1 (quaternary ArC), 134.2 (quaternary ArC).

[α]²⁰_D = +173.8° (c = 1.0, CHCl₃).

An advanced process for large scale (500 g) preparation of a (3Z,5Z)-2,7-dihydro-1H-azepine-derived chiral tridentate ligand (Hamari ligand), widely used for asymmetric synthesis of tailor-made α-amino acids via the corresponding glycine Schiff base Ni(II) complex, is disclosed. The process includes amidation, bis-alkylation, and precipitation/purification of the target compound by TFA as a counterion.

Large Scale Synthesis of Chiral (3Z,5Z)-2,7-Dihydro-1H-azepine-Derived Hamari Ligand for General Asymmetric Synthesis of Tailor-Made Amino Acids

Motohiro Takahashi*^†

, Hiroki Moriwaki^†, Toshio Miwa^†, Brittanie Hoang^‡, Peng Wang^‡, and Vadim A. Soloshonok*^§^∥

^† Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka 533-0024, Japan

^‡ Hamari Chemicals USA, San Diego Research Center, 11494 Sorrento Valley Road, San Diego, California 92121, United States

^§ Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizábal 3, 20018 San Sebastián, Spain

^∥ IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, Plaza Bizkaia, 48013 Bilbao, Spain

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00406

Publication Date (Web): January 18, 2019

*E-mail: motohiro-takahashi@hamari.co.jp., *E-mail: vadym.soloshonok@ehu.es.

This article is part of the Japanese Society for Process Chemistry special issue.

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Kalyan Kumar Pasunooti, Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition

Uncategorized Comments Off

Jan 052019

Itraconazole has been found to possess potent antiangiogenic activity, exhibiting promising antitumor activity in several human clinical studies. The wider use of itraconazole in the treatment of cancer, however, has been limited by its potent inhibition of the drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4). In an effort to eliminate the CYP3A4 inhibition while retaining its antiangiogenic activity, we designed and synthesized a series of derivatives in which the 1,2,4-triazole ring is replaced with various azoles and nonazoles. Among these analogues, 15n with tetrazole in place of 1,2,4-triazole exhibited optimal inhibition of human umbilical vein endothelial cell proliferation with an IC₅₀ of 73 nM without a significant effect on CYP3A4 (EC₅₀ > 20 μM). Similar to itraconazole, 15n induced Niemann-Pick C phenotype (NPC phenotype) and blocked AMPK/mechanistic target of rapamycin signaling. These results suggest that 15n is a promising angiogenesis inhibitor that can be used in combination with most other known anticancer drugs.

Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition

Yingjun Li^†^§, Kalyan Kumar Pasunooti^†^§, Ruo-Jing Li^†, Wukun Liu^†, Sarah A. Head^†, Wei Q. Shi^†

, and Jun O. Liu*^†^‡

^†Department of Pharmacology and Molecular Sciences and ^‡Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States

J. Med. Chem., 2018, 61 (24), pp 11158–11168

DOI: 10.1021/acs.jmedchem.8b01252

Publication Date (Web): November 27, 2018

*E-mail: joliu@jhu.edu. Phone 410-955-4619. Fax 410-955-4520.

https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01252

■ ASSOCIATED CONTENT *S Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.8b01252. Molecular formula strings (CSV) Detail of synthesis procedures; kinetic curve of CYP3A4 enzyme activities; philipin staining of compound 15c, 15g; competition assay of itraconazole photoaffinity probe; and NMR and HPLC chart of representative compounds (PDF)

■ AUTHOR INFORMATION Corresponding Author *E-mail: joliu@jhu.edu. Phone 410-955-4619. Fax 410-955- 4520. ORCID Wei Q. Shi: 0000-0001-5453-1753 Jun O. Liu: 0000-0003-3842-9841 Author Contributions § Y.L. and K.K.P. contributed equally to this work. Notes The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS This work was supported by the National Cancer Institutes (grant R01CA184103) and the Flight Attendant Medical Research Institute

4-(4-(4-(4-(((2S,4R)-2-((1H-Tetrazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)- 1-sec-butyl-1H-1,2,4-triazol-5(4H)-one (15n).

1 H NMR (500 MHz, CDCl3, δH): 8.46 (s, 1H), 7.61 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 9 Hz, 2H), 7.24 (dd, J = 8.5, 2.0 Hz, 1H), 7.03 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H), 5.36 (d, J = 14.0 Hz, 1H), 5.27 (d, J = 14.0 Hz, 1H), 4.38 (t, J = 5.0 Hz, 1H), 4.31−4.27 (m, 1H), 3.95 (dd, J = 8.5, 6.5 Hz, 1H), 3.88−3.83 (m, 2H), 3.53 (dd, J = 9.5, 6.5 Hz, 1H), 3.38 (br s, 4H), 3.26 (br s, 4H), 1.89−1.83 (m, 1H), 1.74−1.69 (m, 1H), 1.39 (d, J = 7.0 Hz, 3H), 0.90 (t, J = 7.5 Hz, 3H).

13C NMR (125 MHz, CDCl3, δC): 162.5, 152.8, 152.7, 152.0, 136.3, 133.9, 133.3, 131.5, 130.1, 129.6, 127.2, 123.6, 116.8, 115.4, 107.4, 74.8, 67.9, 67.6, 56.6, 52.7, 36.5, 31.0, 28.5, 19.2, 10.8.

HRMS (ESI) calcd for C34H37Cl2N9O4, 706.2424; found, 706.2425.

HPLC purity: 95.9%, tR = 10.5 min

Kalyan Kumar Pasunooti,

kalyan kumar <kalyandrf@gmail.com>

Dr. Kalyan Kumar Pasunooti pursued his PhD degree from Nanyang Technological University (NTU) (www.ntu.edu.sg), Singapore (2007 – 2011) in the field of Medicinal, Peptide & Protein chemistry. His graduate research work is focused on “Synthesis of bioactive amino acid building blocks and their applications towards the peptides and glycopeptides.” His have total 16 years of academic and industry experience with major multinationals companies & academic institutions and have worked with many collaborative professors around the globe. He authored with more than 28 international peer-reviewed high impact publications such as PNAS, Wily (Angew Chemie), RSC (Chem Comm and Org Biomol Chem), most of American Chemical Society journals (Journal of American Chemical Society, Org. Lett., ACS Chem Bio, J Comb Chem and Bioconugate Chem) and Elsevier (Tetrahedron Letters) journals which are featured many times in Chem. Eng. News and other journals. He holds American patent while work with Johns Hopkins-School of Medicine, USA and this molecule in phase II clinical trials for treating cancer.

Prior to his graduate studies, he spent 5 years as a research scientist in reputable research organizations namely GVK Bio, India (www.gvkbio.com) (2006-2007) and Dr. Reddy’s Laboratories Ltd (www.drreddys.com) (2003-2006) in India. After his PhD graduation, he worked for world leading research institutes such as Johns Hopkins-School of Medicine, USA (www.hopkinsmedicne.org) (2012-2013), Nanyang Technological University-NTU, Singapore) (www.ntu.edu.sg) (2013 – 2017) and Singapore MIT Alliance for research & Technology-SMART (www.smart.mit.edu) (2017–2018). His research interests focused on development of next generation biologically relevant peptide & protein therapeutics using their newly discovered methodologies for biomedical applications.

He has excellent skills in designing synthesis, purification and characterization of complex peptide and small molecules for medicinal chemistry applications. He gained extensive experience in Medicinal, Carbohydrate, Peptide & Protein and nucleotide & nucleoside Chemistry and familiar with modern methods and experienced in designing & executing synthesis for various bioactive peptide and small molecule inhibitors. He well versed in synthesis and characterization of complex organic molecules and with the analytical data interpretation.

Dr. Kalyan Kumar Pasunooti

Research Scientist at Singapore-MIT Alliance for Research & Technology Centre

Singapore’

Accomplished Peptide, Protein and Medicinal chemist with 16 years of academic and industrialexperience in the field of drug discovery and development. Specializations: Peptide & Protein Chemistry,Medicinal Chemistry (Drug Discovery and Development) and Chemical Biology.

Research Scientist at Singapore-MIT Alliance for Research and Technology

Research Fellow at Nanyang Technological University, Singapore
Former Post-Doctoral Fellow at Johns Hopkins School of Medicine
Studied Physical organic chemistry at PG College of Science, Saifabad/Osmania University
Studied M.P.C at Government Junior College, Hanamkonda
Studied B.Sc. at Kakatiya Government Degree College
Went to Z. P. S. S. Geesugonda

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General Pharmacology

Uncategorized Comments Off

Dec 312018

Top 20 General Pharmacology Questions Every one of us Should Know

*Q.1 What is Pharmacology?*

Ans: Pharmacology is a branch of science that deals with the interaction of drugs with living organisms. Or The study of Pharmacokinetics and Pharmacodynamics.

*Q.2 What is a Drug?*

Ans: A drug is any chemical entity that causes a change in biological function in a living organism.some drugs are formed inside the body such as insulin and noradrenaline etc.drugs that are introduced into the body from outside are called Xenobiotics.

*Q.3 What Is a Dose?*

Ans: A Specific Amount of Drug Prescribed to be taken at one time.

*Q.4 What Is Blood Brain Barrier?*

It is A Tight Endothelial Cells Of the Brain Capillaries And Glial Cells Of The Brain Around The blood capillaries that doesn’t allow the passage of certain lipid insoluble substances to pass from the blood into the brain.Lipid Soluble Drugs can easily Cross This Barrier.Examples Of Lipid soluble Drugs are; Diazepam, Thiopental, And Phenobarbitol.

*Q.5 What is Volume Of Distribution?*

Ans: The total Volume Of The Body Fluid in which a drug appears to be distributed according to its concentration in the blood or plasma.VD of a drug can be determined by the following Formula,

VD (Volume OF Distribution) =Total Amount OF Drug In the Body/Concentration of drug in the blood plasma.

*Q.6 What Is Potency?*

Ans: It is the weight of the drug that produces a certain magnitude of response.For Example Lesser the weight of drug required to produce a given effect, more its potency.Also More the weight of the drug required to produce the same effect lesser its potency.e.g Clonidine Produce its antihypertensive effect in 0.2-0.3mg Daily Dose.While Antihypertensive dose of methyldopa is 500-2000mg Per Day.Thus Clonidine IS more Potent than methyldopa.

*Q.7 What Is Efficacy?*

Ans:If the dose of a drug is increased its effect will be increased proportionately, until a stage is reached beyond there is no further increase in effect will occur,even if a large dose of drug is given.thix maximum effect of drug beyond which no further increase in its effect occurs even if the dose of the drug is increased to a large amount is called efficacy or maximal efficacy.example morphine has more efficacy than aspirin as an analgesic .morphine is more effective in the severe type of pains while aspirin is effective in mild to moderate pain.

*Q.8 What is Therapeutic index?*

The ratio between median toxic dose (TD50) and median effective dose (ED50) is called therapeutic index.

Therapeutic index= TD50/ED50

*Q.9 What is idiosyncrasy?*

It is a rare type of response to a drug that is not related to its dose, that is, even a small dose can cause it.For example.A rare adverse effect with chloramphenicol is aplastic anemia.

*Q.10 What is Hypersensitivity?*

An allergic or immunological response to a drug .for example anaphylactic shock with penicillin is a severe type of hypersensitivity reaction.

*Q.11 What is Tolerance?*

Ans: Repeated use of a drug causes a gradual decrease in the response to the drug.e.g chronic use of morphine will decrease many of its effects in the body, therefore the dose of the drug has to be increased with the passage of time to maintain the usual effects of the drug.

*Q.12 What is a Receptor?*

Ans: Receptor is a macromolecule (Big molecule).Most of the receptors are protein in nature.mostly those drugs that act on the cells bind to the receptors.Those drugs which bind to the receptor and show their effect are called agonists.While some drugs bind to the receptor but don’t produce an effect.These drugs are known as an antagonist as they prevent the binding of agonists with the receptors.

*Q.14 What is the adverse drug reaction?*

Drugs may produce two types of effect i.e Useful effects and harmful effects.harmful effects are also known as adverse drug reaction or undesired effects.These effects may range from the mild type of adverse effect to severe effects that may cause a death of the person.

Adverse drug reaction may be classified into the following types;

Idiosyncrasy

Drug allergy

Direct toxic effect

Drug dependence

Tolerance

*Q.15 What is Shock?*

It is a clinical condition in which there is an inadequate supply of blood to tissues.it causes hypotension, oliguria, and metabolic acidosis.Following are the common types of shock:

A. Hypovolemic shock

B. Septic shock

C. Cardiogenic shock

D. Anaphylactic shock

*Q.16 What is Drug Clearance?*

Ans: It Can be defined as Volume Of blood or plasma cleared of the drug in a unit period of time.Thus, to determine clearance we have to find that volume of blood or plasma from which a drug is removed during a unit period of time.By removal of drug we mean metabolism and excretion of drug.if we know the clearance of a drug we can adjust its dose properly.clearance of the drug can be determined by the following formula.

Cl: Rate of elimination/Concentration of drug in the blood

Where is Cl is clearance?

*Q.17 What is Drug Excretion?*

Ans: Removal of drugs from the body is known as their excretion.Drugs are excreted from the body either in the form of their metabolites or in unchanged form.Excretion can occur from the following routes;

A) Faecal

B) Renal

C) Biliary

D)Pulmonary

E)Others like to sweat, saliva, milk etc

*Q.18 What is Toxicology?*

It is an aspect of pharmacology that deals with the adverse effects of drugs on living organisms .in addition to drugs used in therapy, it also deals with many other chemicals that may be responsible for the household, environmental, or industrial intoxication.

*Q.19 What is antidote?*

Ans: Antidotes are Any Substance which Is Used To oppose the effects of poisons without causing any damage to The body. Example antidote for benzodiazepine is flumazenil.

*Q.20 What is Bioavailability?*

It can be defined as a fraction of unmodified drug reaching into the systemic circulation after it is administered by any route.IV administration of drug produces 100% bioavailability as a whole of the drug enters the systemic circulation.Oral administration of the drug may not produce 100% bioavailability due to incomplete absorption of a drug from the Gastrointestinal tract and due to first pass effects of some of the drugs.

[29/12, 10:20 AM] ‪+91 93017 24365‬: *Sun Pharma arm gets relief from US court in patent infringement case*

_The lawsuit alleged trade secret misappropriation and patent infringement of DUSA’s photodynamic therapy patents covering its product._

: Sun Pharma Wednesday said, DUSA Pharmaceuticals, an arm of of the Mumbai based pharma giant, has received relief from a US court in a patent infringement case.

Massachusetts-based DUSA has been granted preliminary injunctive relief by a federal district court prohibiting defendants Biofrontera Inc, Biofrontera Bioscience GmbH, Biofrontera Pharma GmbH, and Biofrontera AGf from using its confidential and proprietary trade secret information, Sun Pharmaceutical Industries said in a regulatory filing.

Earlier this year, DUSA, which is wholly-owned by Sun Pharma, filed a lawsuit against the Biofrontera defendants in the US District Court for the District of Massachusetts.

The lawsuit alleged trade secret misappropriation and patent infringement of DUSA’s photodynamic therapy patents covering its product.

DUSA, in its amended complaint filed in July 2018, additionally alleged the Biofrontera defendants misappropriated confidential and trade secret information by obtaining confidential information from its former employees to sell and market defendants’ own products.

The lawsuit sought an assessment of both damages and injunctive relief against the Biofrontera defendants, Sun Pharma said.

The court’s order prohibits Biofrontera from making use of or disseminating DUSA’s sales and financial information, customer lists and customer target lists, training and marketing materials, standard operating procedures, technical information, and unpublished clinical data, and any derivations thereof, effective immediately, it added.

[29/12, 10:32 AM] ‪+91 93017 24365‬: **CDSCO tightens safety & labelling rules for acne drug isotretinoin, prescription mandatory*The Central Drugs Standard Control Organisation (CDSCO) has tightened safety guidelines and labelling rules for isotretinoin capsules, an oral drug used for the treatment and prevention of severe acne, citing harmful side effects and adverse reactions. The national drug regulator is learnt to have taken the action following complaints received by the Centralised Public Grievance Redress and Monitoring System.

The stricter regulations for manufacture and retail of isotretinoin were recommended by the CDSCO’s Subject Expert Committee for dermatology and allergy at its recent meeting.

Isotretinoin is an oral derivative of vitamin A. According to clinicians, the medication is prescribed to people who have severe and painful acne that affects their quality of life. The average course of treatment is 4-6 months. It is available in India under various brand names such as Zenatane, Isotroin, Retinon, Aktret, Ratino and Isopad. Many users also obtain the product online.

Isotretinoin’s 10mg and 20mg capsules were approved by the CDSCO way back in 2002 for treatment of severe nodular acne that were unresponsive to antibiotic therapy. The nod was given with various conditions including box warning on packs for female patients as the drug may cause severe birth defects.

Making the rules more rigorous, the national regulator has ordered drug controllers of all states and Union Territories to ensure that the medicine is sold on prescription of dermatologists only. Moreover, chemists should maintain details of the sale as per requirements of Drugs & Cosmetics Rules of 1945.

The drug pack should henceforth carry the following *box warning* : *“This medicine may cause severe birth defects; you must not take this medicine if you are pregnant or may likely become pregnant during treatment. You should also avoid pregnancy for 6 months after stopping the treatment”.*

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Combination of Enantioselective Preparative Chromatography and Racemization: Experimental Demonstration and Model-Based Process Optimization

PROCESS, SYNTHESIS Comments Off

Dec 122018

Conventional enantioselective preparative chromatographic separation using columns packed with chiral stationary phase is characterized by a 50% yield constraint. Racemization of the undesired enantiomer and recycling the formed mixture is an attractive option to tackle this limit. To implement this concept, potential is seen in particular in applying enzymes immobilized in a second fixed bed. However, the identification of suitable operating conditions and the direct connection of a chromatographic column and an enzymatic reactor is not trivial. The paper presents results of an experimental study applying jointly a batch-wise operated chiral Chirobiotic T column to resolve the two enantiomers of mandelic acid (MA) and a mandelate racemase immobilized on Eupergit CM. The general concept could be successfully demonstrated over several cycles focusing on the provision of (S)-MA. A mathematical model was developed in order to illustrate essential process features and to quantitatively describe the coupled separation and racemization processes. The key ingredients of this model, namely, the adsorption isotherms of the two enantiomers on the chiral column and the rate of racemization in the enzymatic reactor, were determined experimentally. The potential of applying the model for further process optimization and generalization is indicated.

Combination of Enantioselective Preparative Chromatography and Racemization: Experimental Demonstration and Model-Based Process Optimization

Katarzyna Wrzosek*^†

, Isabel Harriehausen^†, and Andreas Seidel-Morgenstern^†^‡

^† Max-Planck Institute for Dynamics of Complex Technical System, Physical and Chemical Foundations of Process Engineering, 39106 Magdeburg, Germany

^‡ Otto von Guericke University, Chemical Process Engineering, 39106 Magdeburg, Germany

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00254

*E-mail: wrzosek@mpi-magdeburg.mpg.de. Tel.: +49 391 6110 321.

link https://pubs.acs.org/doi/10.1021/acs.oprd.8b00254

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