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

Absolute Quantification of Lipophilic Shellfish Toxins by Quantitative Nuclear Magnetic Resonance Using Removable Internal Reference Substance with SI Traceability

organic chemistry Comments Off

Jun 282018

Absolute Quantification of Lipophilic Shellfish Toxins by Quantitative Nuclear Magnetic Resonance Using Removable Internal Reference Substance with SI Traceability

Tsuyoshi KATO, Maki SAITO, Mika NAGAE, Kazuhiro FUJITA, Masatoshi WATAI, Tomoji IGARASHI, Takeshi YASUMOTO, and Minoru INAGAKI

Keywords: Lipophilic shellfish toxin, okadaic acid, dinophysistoxin-1, polyethers, qNMR, AQARI

Analytical Sciences, 2016, 32(7), 729.

DOI: 10.2116/analsci.32.729

Read abstract
View this article in J-STAGE
Okadaic acid (OA), a lipophilic shellfish toxin, was accurately quantified using quantitative nuclear magnetic resonance with internal standards for the development of an authentic reference standard. Pyridine and the residual proton in methanol-d₄ were used as removable internal standards to limit any contamination. They were calibrated based on a maleic acid certified reference material. Thus, the concentration of OA was traceable to the SI units through accurate quantitative NMR with an internal reference substance. Signals from the protons on the oxygenated and unsaturated carbons of OA were used for quantification. A reasonable accuracy was obtained by integrating between the lower and upper ¹³C satellite signal range when more than 4 mg of OA was used. The best-determined purity was 97.4% (0.16% RSD) when 20 mg of OA was used. Dinophysistoxin-1, a methylated analog of OA having an almost identical spectrum, was also quantified by using the same methodology.

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Amelioration of diethylnitrosamine (DEN)-induced hepatocellular carcinogenesis in animal models via knockdown oxidative stress and proinflammatory markers by Madhuca longifolia embedded silver nanoparticles

nanotechnology, Uncategorized Comments Off

Jun 122018

Amelioration of diethylnitrosamine (DEN)-induced hepatocellular carcinogenesis in animal models via knockdown oxidative stress and proinflammatory markers by Madhuca longifolia embedded silver nanoparticles

http://pubs.rsc.org/en/content/articlepdf/2018/ra/c7ra12775h

DOI: 10.1039/c7ra12775h

rsc.li/rsc-advances

RSC Adv., 2018, 8, 6940–6953

Deepika Singh, a Manvendra Singh,b Ekta Yadav,a Neha Falls,a Ujendra Komal,c Deependra Singh Dangi,d Vikas Kumare and Amita Verma*f

Department of Pharmaceutical Science, Faculty of Health Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Allahabad, 211007, India

b HMFA Institute of Engineering & Technology, Handia, Allahabad, 211007, India

c Department of Mechanical & Industrial Engineering, Indian Institute of Technology, Roorkee, Uttrakhand, India

d Kinapse India Scientic Services Pvt. Ltd., Gurgoan, Haryana, India

e Natural Product Drug Discovery Laboratory, Department of Pharmaceutical Sciences, Faculty of Health Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Allahabad, Uttar Pradesh 211007, India

f Bio-organic & Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Faculty of Health Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Allahabad – 211007, Uttar Pradesh, India.

E-mail: amitaverma.dr@gmail.com; amita.verma@shiats.edu.in

In hepatocellular carcinoma (HCC), primary liver cancer is primarily responsible for inflammation-related cancer as more than 90% of HCCs emerge with regard to hepatic damage and inflammation. Tenacious inflammation is known to advance and intensify liver tumours. Nanomaterials, for example, silver nanoparticles synthesized from plant-derived materials have shown great outcomes in reducing the precancerous nodules and have anticancer properties. The aim of the present investigation was to biosynthesize, characterize and evaluate the anticancer activity of nanoparticles-embedded Madhuca longifolia extract (MLAgNPs) on an experimental model of hepatic cancer in rats. M. longifolia contains a high amount of flavonoids and other phenolic derivative. The silver nanoparticles synthesized by M. longifolia were characterized by various instruments, including UV-Vis spectrophotometry, X-ray beam diffraction, field-emission scanning electron microscopy with energy dispersive X-ray analysis, transmission electron microscopy and Fourier transform infrared spectroscopy. Liver cancer was induced to 36 Wistar rats by a single dose of diethylnitrosamine (DEN) (200 mg kg1 BW). Hepatic cancer by MLAgNPs dose-dependently limited macroscopical variation compared with the DEN-induced hepatic cancer groups. The serum and liver were taken to measure the antioxidant parameters, proinflammatory cytokines and for a histopathological study. Serum hepatic and serum non-hepatic along with inflammatory cytokines were also assessed. Reduction in the levels of proinflammatory cytokines, namely tumour necrosis factor-a, interleukin-6, interleukin-1b, nuclear factor kappa beta (NF-kB), and improved membrane-bound enzyme activity were also detected. It was found that minor morphological anomalies were identified in the histopathology analysis in the MLAgNPs-treated groups. It could be concluded that silver nanoparticles introduce an extraordinary potential for use as adjuvants in hepatic cancer treatment because of their antioxidant abilities and ability to diminish inflammation in liver tissue by attenuating the NF-kB pathway.

Conclusion Our outcomes have demonstrated that the bioengineered silver nanoparticles of M. longifolia leaves extract cause in vitro and in vivo apoptosis of hepatic cancer through an ROS pathway and are promising agents in liver carcinogenesis.

DR AMITA VERMA

Professor at Sam Higginbottom University of Agriculture, Technology and Sciences
Studied Ph.D at Jamia Hamdard University

Bio-organic & Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Faculty of Health Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Allahabad – 211007, Uttar Pradesh, India.

E-mail: amitaverma.dr@gmail.com; amita.verma@shiats.edu.in

Sam Higginbottom University of Agriculture, Technology and Sciences

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Expansion of First-in-Class Drug Candidates That Sequester Toxic All-Trans-Retinal and Prevent Light-Induced Retinal Degeneration s

Uncategorized Comments Off

Jun 042018

ABSTRACT All-trans-retinal, a retinoid metabolite naturally produced upon photoreceptor light activation, is cytotoxic when present at elevated levels in the retina. To lower its toxicity, two experimentally validated methods have been developed involving inhibition of the retinoid cycle and sequestration of excess of all-trans-retinal by drugs containing a primary amine group. We identified the first-in-class drug candidates that transiently sequester this metabolite or slow down its production by inhibiting regeneration of the visual chromophore, 11-cis-retinal. Two enzymes are critical for retinoid recycling in the eye. Lecithin:retinol acyltransferase (LRAT) is the enzyme that traps vitamin A (all-trans-retinol) from the circulation and photoreceptor cells to produce the esterified substrate for retinoid isomerase (RPE65), which converts all-trans-retinyl ester into 11-cis-retinol. Here we investigated retinylamine and its derivatives to assess their inhibitor/substrate specificities for RPE65 and LRAT, mechanisms of action, potency, retention in the eye, and protection against acute light-induced retinal degeneration in mice. We correlated levels of visual cycle inhibition with retinal protective effects and outlined chemical boundaries for LRAT substrates and RPE65 inhibitors to obtain critical insights into therapeutic properties needed for retinal preservation.

http://molpharm.aspetjournals.org/content/early/2014/12/23/mol.114.096560

Expansion of First-in-class Drug Candidates that Sequester Toxic All-trans-retinal and Prevent Light-induced Retinal Degeneration

, Zhiqian Dong, Sreenivasa Mundla, X Eric Hu, , , and Marcin Golczak

Molecular Pharmacology December 23, 2014, mol.114.096560; DOI: https://doi.org/10.1124/mol.114.096560

Sreeni Labs Private Limited, Hyderabad, India is ready to take up challenging synthesis projects from your preclinical and clinical development and supply from few grams to multi-kilo quantities. Sreeni Labs has proven route scouting ability to design and develop innovative, cost effective, scalable routes by using readily available and inexpensive starting materials. The selected route will be further developed into a robust process and demonstrate on kilo gram scale and produce 100’s of kilos of in a relatively short time.

Accelerate your early development at competitive price by taking your route selection, process development and material supply challenges (gram scale to kilogram scale) to Sreeni Labs…………

INTRODUCTION

Sreeni Labs based in Hyderabad, India is working with various global customers and solving variety of challenging synthesis problems. Their customer base ranges from USA, Canada, India and Europe. Sreeni labs Managing Director, Dr. Sreenivasa Reddy Mundla has worked at Procter & Gamble Pharmaceuticals and Eli Lilly based in USA.

The main strength of Sreeni Labs is in the design, development of innovative and highly economical synthetic routes and development of a selected route into a robust process followed by production of quality product from 100 grams to 100s of kg scale. Sreeni Labs main motto is adding value in everything they do.

They have helped number of customers from virtual biotech, big pharma, specialty chemicals, catalog companies, and academic researchers and drug developers, solar energy researchers at universities and institutions by successfully developing highly economical and simple chemistry routes to number of products that were made either by very lengthy synthetic routes or by using highly dangerous reagents and Suzuki coupling steps. They are able to supply materials from gram scale to multi kilo scale in a relatively short time by developing very short and efficient synthetic routes to a number of advanced intermediates, specialty chemicals, APIs and reference compounds. They also helped customers by drastically reducing number of steps, telescoping few steps into a single pot. For some projects, Sreeni Labs was able to develop simple chemistry and avoided use of palladium & expensive ligands. They always begin the project with end in the mind and design simple chemistry and also use readily available or easy to prepare starting materials in their design of synthetic routes

Over the years, Sreeni labs has successfully made a variety of products ranging from few mg to several kilogram scale. Sreeni labs has plenty of experience in making small select libraries of compounds, carbocyclic compounds like complex terpenoids, retinal derivatives, alkaloids, and heterocyclic compounds like multi substituted beta carbolines, pyridines, quinolines, quinolones, imidazoles, aminoimidazoles, quinoxalines, indoles, benzimidazoles, thiazoles, oxazoles, isoxazoles, carbazoles, benzothiazoles, azapines, benzazpines, natural and unnatural aminoacids, tetrapeptides, substituted oligomers of thiophenes and fused thiophenes, RAFT reagents, isocyanates, variety of ligands, heteroaryl, biaryl, triaryl compounds, process impurities and metabolites.

Sreeni Labs is Looking for any potential opportunities where people need development of cost effective scalable routes followed by quick scale up to produce quality products in the pharmaceutical & specialty chemicals area. They can also take up custom synthesis and scale up of medchem analogues and building blocks. They have flexible business model that will be in sink with customers. One can test their abilities & capabilities by giving couple of PO based (fee for service) projects.

Some of the compounds prepared by Sreeni labs;

See presentation below

LINK ON SLIDESHARE

Sreeni Labs Profile from Sreenivasa Reddy

Managing Director at Sreeni Labs Private Limited

Few Case Studies : Source SEEENI LABS

QUOTE………….

One virtual biotech company customer from USA, through a common friend approached Sreeni Labs and told that they are buying a tetrapeptide from Bachem on mg scale at a very high price and requested us to see if we can make 5g. We accepted the challenge and developed solution phase chemistry and delivered 6g and also the process procedures in 10 weeks time. The customer told that they are using same procedures with very minor modifications and produced the tetrapeptide ip to 100kg scale as the molecule is in Phase III.

One East coast customer in our first meeting told that they are working with 4 CROs of which two are in India and two are in China and politely asked why they should work with Sreeni Labs. We told that give us a project where your CROs failed to deliver and we will give a quote and work on it. You pay us only if we deliver and you satisfy with the data. They immediately gave us a project to make 1.5g and we delivered 2g product in 9 weeks. After receiving product and the data, the customer was extremely happy as their previous CRO couldn’t deliver even a milligram in four months with 3 FTEs.

One Midwest biotech company was struggling to remove palladium from final API as they were doing a Suzuki coupling with a very expensive aryl pinacol borane and bromo pyridine derivative with an expensive ligand and relatively large amount of palldium acetate. The cost of final step catalyst, ligand and the palladium scavenging resin were making the project not viable even though the product is generating excellent data in the clinic. At this point we signed an FTE agreement with them and in four months time, we were able to design and develop a non suzuki route based on acid base chemistry and made 15g of API and compared the analytical data and purity with the Suzuki route API. This solved all three problems and the customer was very pleased with the outcome.

One big pharma customer from east coast, wrote a structure of chemical intermediate on a paper napkin in our first meeting and asked us to see if we can make it. We told that we can make it and in less than 3 weeks time we made a gram sample and shared the analytical data. The customer was very pleased and asked us to make 500g. We delivered in 4 weeks and in the next three months we supplied 25kg of the same product.

Through a common friend reference, a European customer from a an academic institute, sent us an email requesting us to quote for 20mg of a compound with compound number mentioned in J. med. chem. paper. It is a polycyclic compound with four contiguous stereogenic centers. We gave a quote and delivered 35 mg of product with full analytical data which was more pure than the published in literature. Later on we made 8g and 6g of the same product.

One West coast customer approached us through a common friend’s reference and told that they need to improve the chemistry of an advanced intermediate for their next campaign. At that time they are planning to make 15kg of that intermediate and purchased 50kg of starting raw material for $250,000. They also put five FTEs at a CRO for 5 months to optimize the remaining 5 steps wherein they are using LAH, Sodium azide, palladium catalyst and a column chromatography. We requested the customer not to purchase the 50kg raw material, and offered that we will make the 15kg for the price of raw material through a new route in less than three months time. You pay us only after we deliver 15 kg material. The customer didn’t want to take a chance with their timeline as they didn’t work with us before but requested us to develop the chemistry. In 7 weeks time, we developed a very simple four step route for their advanced intermediate and made 50g. We used very inexpensive and readily available starting material. Our route gave three solid intermediates and completely eliminated chromatographic purifications.

One of my former colleague introduced an academic group in midwest and brought us a medchem project requiring synthesis of 65 challenging polyene compounds on 100mg scale. We designed synthetic routes and successfully prepared 60 compounds in a 15 month time.

UNQUOTE…………

The man behind Seeni labs is Dr.Sreenivasa Reddy Mundla

Sreenivasa Reddy

Dr. Sreenivasa Reddy Mundla

Managing Director at Sreeni Labs Private Limited

Sreeni Labs Private Limited

Road No:12, Plot No:24,25,26

IDA, Nacharam
Hyderabad, 500076
Telangana State, India

Links

LINKEDIN https://in.linkedin.com/in/sreenivasa-reddy-10b5876

FACEBOOK https://www.facebook.com/sreenivasa.mundla

RESEARCHGATE https://www.researchgate.net/profile/Sreenivasa_Mundla/info

EMAIL mundlasr@hotmail.com, Info@sreenilabs.com, Sreeni@sreenilabs.com

Phone :+91-9866092626, India

Dr. Sreenivasa Mundla Reddy

Dr. M. Sreenivasa Reddy obtained Ph.D from University of Hyderabad under the direction Prof Professor Goverdhan Mehta in 1992. From 1992-1994, he was a post doctoral fellow at University of Wisconsin in Professor Jame Cook’s lab. From 1994 to 2000, worked at Chemical process R&D at Procter & Gamble Pharmaceuticals (P&G). From 2001 to 2007 worked at Global Chemical Process R&D at Eli Lilly and Company in Indianapolis.

In 2007 resigned to his job and founded Sreeni Labs based in Hyderabad, Telangana, India and started working with various global customers and solving various challenging synthesis problems.
The main strength of Sreeni Labs is in the design, development of a novel chemical route and its development into a robust process followed by production of quality product from 100 grams to 100’s of kg scale.

They have helped number of customers by successfully developing highly economical simple chemistry routes to number of products that were made by Suzuki coupling. they are able to shorten the route by drastically reducing number of steps, avoiding use of palladium & expensive ligands. they always use readily available or easy to prepare starting materials in their design of synthetic routes.

Sreeni Labs is Looking for any potential opportunities where people need development of cost effective scalable routes followed by quick scale up to produce quality products in the pharmaceutical & specialty chemicals area. They have flexible business model that will be in sink with customers. One can test their abilities & capabilities by giving PO based projects

Experience

Founder & Managing Director

Sreeni Labs Private Limited

August 2007 – Present (8 years 11 months)

Sreeni Labs Profile

View On SlideShare

Principal Research Scientist

Eli Lilly and Company

March 2001 – August 2007 (6 years 6 months)

Senior Research Scientist

Procter & Gamble

July 1994 – February 2001 (6 years 8 months)

Education

University of Wisconsin-Milwaukee

PDF, Synthetic Organic Chemistry

1992 – 1994

University of Hyderabad

Doctor of Philosophy (Ph.D.),

1986 – 1992

Hari Krishna Santhapuram

With Sreenivasa Mundla, Narahara sastry, Ram Kishan Rao, Jagadeesh Bharatam, Jagadish Gunjur and Jagadish Bharatham.

PUBLICATIONS

Article: Expansion of First-in-Class Drug Candidates That Sequester Toxic All-Trans-Retinal and Prevent Light-Induced Retinal Degeneration

Jianye Zhang · Zhiqian Dong · Sreenivasa Reddy Mundla · X Eric Hu · William Seibel ·Ruben Papoian · Krzysztof Palczewski · Marcin Golczak

Article: ChemInform Abstract: Regioselective Synthesis of 4Halo ortho-Dinitrobenzene Derivative

Sreenivasa Mundla

Aug 2010 · ChemInform

Article: Optimization of a Dihydropyrrolopyrazole Series of Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors: Discovery of an Orally Bioavailable Transforming Growth Factor-β Receptor Type I Inhibitor as Antitumor Agent

Hong-yu Li · William T. McMillen · Charles R. Heap · Denis J. McCann · Lei Yan · Robert M. Campbell · Sreenivasa R. Mundla · Chi-Hsin R. King · Elizabeth A. Dierks · Bryan D. Anderson · Karen S. Britt · Karen L. Huss

Apr 2008 · Journal of Medicinal Chemistry

Article: ChemInform Abstract: A Concise Synthesis of Quinazolinone TGF-β RI Inhibitor Through One-Pot Three-Component Suzuki—Miyaura/Etherification and Imidate—Amide Rearrangement Reactions

Hong-yu Li · Yan Wang · William T. McMillen · Arindam Chatterjee · John E. Toth ·Sreenivasa R. Mundla · Matthew Voss · Robert D. Boyer · J. Scott Sawyer

Feb 2008 · ChemInform

Article: ChemInform Abstract: A Concise Synthesis of Quinazolinone TGF-β RI Inhibitor Through One-Pot Three-Component Suzuki—Miyaura/Etherification and Imidate—Amide Rearrangement Reactions

Hong-yu Li · Yan Wang · William T. McMillen · Arindam Chatterjee · John E. Toth ·Sreenivasa R. Mundla · Matthew Voss · Robert D. Boyer · J. Scott Sawyer

Nov 2007 · Tetrahedron

Article: Dihydropyrrolopyrazole Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors: A Novel Benzimidazole Series with Selectivity versus Transforming Growth Factor-β Type II Receptor Kinase and Mixed Lineage Kinase-7

Hong-yu Li · Yan Wang · Charles R Heap · Chi-Hsin R King · Sreenivasa R Mundla · Matthew Voss · David K Clawson · Lei Yan · Robert M Campbell · Bryan D Anderson · Jill R Wagner ·Karen Britt · Ku X Lu · William T McMillen · Jonathan M Yingling

Apr 2006 · Journal of Medicinal Chemistry

Read full-text, Source

Article: Studies on the Rh and Ir mediated tandem Pauson–Khand reaction. A new entry into the dicyclopenta[ a, d]cyclooctene ring system

Hui Cao · Sreenivasa R. Mundla · James M. Cook

Aug 2003 · Tetrahedron Letters

Article: ChemInform Abstract: A New Method for the Synthesis of 2,6-Dinitro and 2Halo6-nitrostyrenes

Sreenivasa R. Mundla

Nov 2000 · ChemInform

Article: ChemInform Abstract: A Novel Method for the Efficient Synthesis of 2-Arylamino-2-imidazolines

Sreenivasa R. Mundla · Larry J. Wilson · Sean R. Klopfenstein · William L. Seibel · Nick N. Nikolaides

Nov 2000 · ChemInform

Article: A new method for the synthesis of 2,6-dinitro and 2-halo-6-nitrostyrenes

Sreenivasa R Mundla

Aug 2000 · Tetrahedron Letters

Read full-text, Source

Article: A Novel Method for the Efficient Synthesis of 2-Arylamino-2-imidazolines

Sreenivasa R Mundla · Larry J Wilson · Sean R Klopfenstein · William L. Seibel · Nick N Nikolaides

Aug 2000 · Tetrahedron Letters

Download

Read full-text, Source

Article: Regioselective Synthesis of 4-Halo ortho-Dinitrobenzene Derivatives

Sreenivasa R Mundla

Jun 2000 · Tetrahedron Letters

Download Follow

Article: Synthesis and Evaluation of Analogues of the Partial Agonist 6-(Propyloxy)-4-(methoxymethyl)-β-carboline-3-carboxylic Acid Ethyl Ester (6-PBC) and the Full Agonist 6-(Benzyloxy)-4-(methoxymethyl)-β- carboline-3-carboxylic Acid Ethyl Ester (Zk 93423) at Wild Type and Recombinant GABA A Receptors

Eric D. Cox · Hernando Diaz-Arauzo · Qi Huang · Mundla S. Reddy · Chunrong Ma · Brad Harris · Ruth McKernan · Phil Skolnick · James M. Cook

Aug 1998 · Journal of Medicinal Chemistry

Read at

[LINK]

Patents by Inventor Dr. Sreenivasa Reddy Mundla

TGF-? inhibitors

Patent number: 7872020

Abstract: The present invention provides crystalline 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro -4H-pyrrolo[1,2-b]pyrazole monohydrate.

Type: Grant

Filed: June 29, 2006

Date of Patent: January 18, 2011

Assignee: Eli Lilly and Company

Inventor: Sreenivasa Reddy Mundla
TGF-BETA INHIBITORS

Publication number: 20100120854

Abstract: The present invention provides crystalline 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole monohydrate.

Type: Application

Filed: June 29, 2006

Publication date: May 13, 2010

Applicant: ELI LILLY AND COMPANY

Inventor: Sreenivasa Reddy Mundla
Process for making 2-amino-2-imidazoline, guanidine and 2-amino-3,4,5,6-tetrahydropyrimidine derivatives

Patent number: 6066740

Abstract: The present invention provides a process for making 2-amino-2-imidazoline, guanidine, and 2-amino-3,4,5,6-tetrahydroyrimidine derivatives by preparing the corresponding activated 2-thio-subsituted-2-derivative in a two-step, one-pot procedure and by further reacting yields this isolated derivative with the appropriate amine or its salts in the presence of a proton source. The present process allows for the preparation of 2-amino-2-imidazolines, quanidines, and 2-amino-3,4,5,6-tetrahydropyrimidines under reaction conditions that eliminate the need for lengthy, costly, or multiple low yielding steps, and highly toxic reactants. This process allows for improved yields and product purity and provides additional synthetic flexibility.

Type: Grant

Filed: November 25, 1997

Date of Patent: May 23, 2000

Assignee: The Procter & Gamble Company

Inventors: Michael Selden Godlewski, Sean Rees Klopfenstein, Sreenivasa Reddy Mundla, William Lee Seibel, Randy Stuart Muth

TGF-β inhibitors

US 7872020 B2

Sreenivasa Reddy Mundla

The present invention provides 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl) -5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole monohydrate, i.e., Formula I.

EXAMPLE 1 Preparation of 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl-5,6-dihydro-4H -pyrrolo[1,2-b]pyrazole monohydrate

Galunisertib

¹H NMR (CDCl₃): δ=9.0 ppm (d, 4.4 Hz, 1H); 8.23-8.19 ppm (m, 2H); 8.315 ppm (dd, 1.9 Hz, 8.9 Hz, 1H); 7.455 ppm (d, 4.4 Hz, 1H); 7.364 ppm (t, 7.7 Hz, 1H); 7.086 ppm (d, 8.0 Hz, 1H); 6.969 ppm (d, 7.7 Hz, 1H); 6.022 ppm (m, 1H); 5.497 ppm (m, 1H); 4.419 ppm (t, 7.3 Hz, 2H); 2.999 ppm (m, 2H); 2.770 ppm (p, 7.2 Hz, 7.4 Hz, 2H); 2.306 ppm (s, 3H); 1.817 ppm (m, 2H). MS ES+: 370.2; Exact: 369.16

ABOVE MOLECULE IS

https://newdrugapprovals.org/2016/05/04/galunisertib/

Galunisertib

A TGF-beta receptor type-1 inhibitor potentially for the treatment of myelodysplastic syndrome (MDS) and solid tumours.

LY-2157299

CAS No.700874-72-2

READ MY PRESENTATION ON

Accelerating Generic Approvals, see how you can accelerate your drug development programme

Accelerating Generic Approvals by Dr Anthony Crasto

Accelerating Generic Approvals by Dr Anthony Crasto from Anthony Melvin Crasto Ph.D

KEYWORDS Sreenivasa Mundla Reddy, Managing Director, Sreeni Labs Private Limited, Hyderabad, Telangana, India, new, economical, scalable routes, early clinical drug development stages, Custom synthesis, custom manufacturing, drug discovery, PHASE 1, PHASE 2, PHASE 3, API, drugs, medicines

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Catalysts for assymetric alkylation and isomerisation reactions

SYNTHESIS Comments Off

Jun 042018

+91- 999-997-2051

info@synthesiswithcatalysts.com

Website

http://www.synthesiswithcatalysts.com/

+91- 999-997-2051

info@synthesiswithcatalysts.com

Website

http://www.synthesiswithcatalysts.com/

bpk@synthesiswithcatalysts.com

Axay Parmar

Founder at Synthesis with Catalysts Pvt. Ltd, axayrp@gmail.com

Basu Agarwal and Dr Razi Abdi

shr@synthesiswithcatalysts.com, ba@synthesiswithcatalysts.com

Synthesis with Catalysts Pvt Ltd was founded with an aim to help aromatic chemical, essential oil, pharmaceutical, API manufacturers to develop new products, increase productivity and improve production methodologies.

We have an advanced research and development centre where we innovate new chemical processes and improve the existing ones and help our customers implement the same. We support our research with pilot production of the products.

We are also developing precious metal complexes, Catalysts, Legends etc.

We are continuously working to reset standards of purity with our products.

The team at Synthesis with Catalysts Pvt Ltd has an vast experience and well renowned scientists of India have found it suitable to continue their Research in our facilities. The team with Synthesis with Catalysts Pvt Ltd has presented countless number of research papers all across the world.

We have a world class lab with all advance analytical testing machines.

RESEARCH & DEVELOPMENT

Synthesis with Catalysts Pvt Ltd.’s strength lies in its state-of- the-art infrastructure and R&D capabilities. Innovative process development is the foundation of SWC’s success. Our team of highly qualified R&D experts in process of research and technology development work 24 hours for inventing new processes and Optimizing product development capabilities. Our main focus is developing innovative processes, which could help our partners in reducing their costs and production time. Our Scientists constantly work for cost-effective ways of developing products, ensuring better service for our clients.

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Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite

Uncategorized Comments Off

May 272018

Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.8b00565

Pronay Das, Palak Babbar, Nipun Malhotra, Manmohan Sharma, Gorakhnath R Jachak, Rajesh G. Gonnade, Dhanasekaran Shanmugam, Karl Harlos, Manickam Yogavel, amit sharma, and D. Srinivasa Reddy

Pronay Das†ab, Palak Babbar†c, Nipun Malhotra†c, Manmohan Sharmac , Goraknath R. Jachakab , Rajesh G. Gonnadebd, Dhanasekaran Shanmugambe, Karl Harlosf , Manickam Yogavelc , Amit Sharmac *, and D. Srinivasa Reddyab* †All three have contributed equally to this work.

aOrganic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India

b Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India

cMolecular Medicine Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi 110067, India dCenter for Material Characterization, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India

e Biochemical Sciences Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India

fDivision of Structural Biology, Welcome Trust Centre for Human Genetics, The Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK

J. Med. Chem., Just Accepted Manuscript

DOI: 10.1021/acs.jmedchem.8b00565

Publication Date (Web): May 21, 2018

The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral centre anti-malarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme- and structure-based assays.

We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency where changes at C3 are sensed by rotameric flipping of Glutamate332.

Given that scores of anti-malarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of anti-microbial drug development.

Cladosporin (12) displays exquisite selectivity for the parasite lysyl-tRNA synthetase over human enzyme. This species specific selectivity of cladosporin has been previously described through comprehensive sequence alignment, where the residues val329 and ser346 seem to be sterically crucial for accommodating the methyl moiety of THP ring10. The structural features of compound 12 clearly indicate the presence of three stereocenters, and therefore 2n (n=3) i.e., eight stereoisomers are possible (Fig.1). Till date, only one asymmetric total synthesis of cladosporin13 has been achieved which was followed by another report of formal syntheses14. Here, we have developed a general chemical synthesis route to synthetically access all the eight possible stereoisomers of compound 12.

cladosporin (compound 12) (0.052 g) as a white solid with a yield of 54 %. Melting point: 171-173 °C; [α]25 D = -15.75 (c = 0.6, EtOH); IR υmax(film): cm-1 3416, 3022, 1656, 1218; 1H NMR (400 MHz, CDCl3): δ 11.06 (s, 1H), 7.47 (br. s., 1H), 6.29 (s, 1H), 6.16 (s, 1H), 4.68 (t, J = 9.8 Hz, 1H), 4.12 (s, 1H), 4.01 (s, 1H), 2.89 – 2.75 (m, 2H), 2.00 – 1.94 (m, 1H), 1.87 – 1.81 (m, 1H), 1.70 – 1.63 (m, 4H), 1.35 (d, J = 6.1 Hz, 2H), 1.23 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 169.9, 164.3, 163.1, 141.8, 106.7, 102.0, 101.5, 76.3, 68.0, 66.6, 39.3, 33.6, 30.9, 18.9, 18.1; HRMS calculated for C16H21O5 [M + H]+ 293.1384, observed 293.1379.

Dr. D. Srinivasa Reddy has been appointed as an editor of Bioorganic & Medicinl Chemistry Letters, Elsevier Publications. Congratulation Sir !

Click here for details. https://www.journals.elsevier.com/bioorganic-and-medicinal-chemistry-letters

The research interests of his group lie in issues related to application of oriented organic synthesis, in particular total synthesis of biologically active natural products, medicinal chemistry and crop protection. This team has been credited with having accomplished total synthesis of more than 25 natural products with impressive biological activities. “Some of our recent achievements include identification of potential leads, like antibiotic compound based on hunanamycin natural product for treating food infections, anti-diabetic molecule in collaboration with an industry partner and anti-TB compound using a strategy called ‘re-purposing of a drug scaffold’,” said Reddy.

A total of two awardees out of four were from CSIR institutes. In addition to Reddy, Rajan Shankarnarayanan, CSIR – CCMB, Hyderabad (basic sciences), also was conferred with the award. Vikram Mathews, CMC, Vellore (medical research) and Prof Ashish Suri, AIIMS, New Delhi (clinical research), were the others to receive the awards.

With more than 80 scientific publications and 35 patents, Reddy is one of the most prominent scientists in the city and has already been honoured with the Shanti Swarup Bhatnagar prize in chemical sciences. Reddy is also a nominated member of the scientific body of Indian Pharmacopoeia, government of India and was elected as a fellow of the Telangana and Maharashtra Academies of Sciences in addition to the National Academy of Sciences, India (NASI).

//////////CLADOSPORIN, NCL, CSIR, SRINIVASA REDDY, PUNE, MALARIA

Asymmetric Organocatalysis in Drug Development—Highlights of Recent Patent Literature

green chemistry, SYNTHESIS Comments Off

May 242018

Enantioselective organocatalytic reactions published in the recent patent literature are highlighted in this review and include inter- and intramolecular phase-transfer conjugate additions catalyzed by quaternized cinchona alkaloids, a Diels–Alder reaction catalyzed by oxazaborolidine complexes, asymmetric Betti reactions, the Lonza synthesis of l-carnitine, and several Corey–Bakshi–Shibata reductions.

Asymmetric Organocatalysis in Drug Development—Highlights of Recent Patent Literature

David L. Hughes*

Cidara Therapeutics, Inc., 6310 Nancy Ridge Drive, Suite 101, San Diego, California 92121, United States

Org. Process Res. Dev., 2018, 22 (5), pp 574–584

DOI: 10.1021/acs.oprd.8b00096

Publication Date (Web): April 19, 2018

*E-mail: dhughes@cidara.com.

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00096

///////////////Asymmetric Organocatalysis

What are the drugs of the future?

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May 032018

A cartoon representing how, in history, we are continuously faced with new scientific advancements that make us question what the future holds and whether what we currently have is still useful or should be replaced.

What are the drugs of the future?

Med. Chem. Commun., 2018, Advance Article
DOI: 10.1039/C8MD90019A, Opinion

Huy X. Ngo, Sylvie Garneau-Tsodikova
Are small molecules or biologics the drugs of the future?

What are the drugs of the future?

http://pubs.rsc.org/en/Content/ArticleLanding/2018/MD/C8MD90019A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FMD+%28RSC+-+Med.+Chem.+Commun.+latest+articles%29#!divAbstract

Huy X. Ngo*^a and Sylvie Garneau-Tsodikova*^a

Author affiliations

* Corresponding authors

^a University of Kentucky, 789 South Limestone Street, Lexington, USA
E-mail: huy.ngo@uky.edu, sylviegtsodikova@uky.edu

Abstract

Are small molecules or biologics the drugs of the future? Small-molecule drugs have historically been the pillars of traditional medicine. However, recently, we seem to be amidst a scientific revolution with the rise of many FDA-approved biologic drugs. This opinion article looks at the current state of small molecules and biologics and assesses what the future holds for these two broad classes of drugs.

Are small molecules or biologics the drugs of the future? Let’s think about this… (Fig. 1). For many of us growing up in the 20th century, videotapes were fixtures of our childhoods. In the current entertainment industry, videotapes have completely become obsolete and been replaced by more complex and sophisticated Blu-ray Discs, which deliver ultra high-definition pictures and films to viewers. Technological change is inevitable in our society, which embraces innovations. Similarly, the pharmaceutical industry has been experiencing its own scientific revolution, as more and more novel biologic drugs continue to emerge. Are these biologics the Blu-ray Discs of the pharmaceutical industry? Will smallmolecule drugs fade into history like videotapes did? In an attempt to address these questions, we will compare and contrast small-molecule and biologic drugs to assess what roles they will serve in our healthcare system in the future

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1,2 Diaminocyclohexane from Synthesis with Catalysts Pvt Ltd

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tert-butyl (N-[3-[(3S,4R)-3-amino-4-fluoro-4-(hydroxymethyl)tetrahydrofuran-3-yl]-4-fluorophenyl]acetamide)

ANTHONY CRASTO, spectroscopy, SYNTHESIS Comments Off

Apr 272018

tert-butyl (N-[3-[(3S,4R)-3-amino-4-fluoro-4-(hydroxymethyl)tetrahydrofuran-3-yl]-4-fluorophenyl]acetamide)

1H-NMR (500 MHz, DMSO-d6): 1.31 (s, 9H), 2.02 (s, 3H), 3.21 (m, 1H), 3.88 (m, 1H), 3.94 (m, 1H), 4.03 (m, 1H), 4.13 (m, 1H), 4.74 (m, 1H), 5.07 (m, 1H), 7.08 (m, 1H), 7.43 (bs, 1H), 7.63 (m, 1H), 7.67 (m, 1H), 10.03 (s, 1H) .

13C-NMR (125 MHz, DMSO-d6): 24.3, 28.5, 60.8, 65.1, 72.6, 78.1, 78.9, 105.8, 116.4, 119.7, 120.8, 127.2, 136.2, 155.2, 156.4, 168.7.

19F-NMR (470.6 MHz, DMSO-d6): -164.77, -117.26.

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Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00069

Pressurized CO2 as a carboxylating agent for the biocatalytic ortho-carboxylation of resorcinol

green chemistry Comments Off

Apr 242018

Green Chem., 2018, 20,1754-1759
DOI: 10.1039/C8GC00008E, Communication

Open Access

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.

Katharina Plasch, Gerhard Hofer, Walter Keller, Sam Hay, Derren J. Heyes, Alexander Dennig, Silvia M. Glueck, Kurt Faber
Utilization of gaseous carbon dioxide as a C₁-building block in the biocatalytic ortho-carboxylation of a phenol.
The content of this RSS Feed (c) The Royal Society of Chemistry

http://pubs.rsc.org/en/content/articlehtml/2018/gc/c8gc00008e

Pressurized CO2 as a carboxylating agent for the biocatalytic ortho-carboxylation of resorcinol

Pressurized CO₂ as a carboxylating agent for the biocatalytic ortho-carboxylation of resorcinol

Katharina Plasch,^a Gerhard Hofer,^b Walter Keller,^b Sam Hay,^c Derren J. Heyes,^c Alexander Dennig,^d Silvia M. Glueck*^a^e and Kurt Faber*^a

Author affiliations

* Corresponding authors

^a Department of Chemistry, Organic & Bioorganic Chemistry, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
E-mail:Si.Glueck@Uni-Graz.at, Kurt.Faber@Uni-Graz.at

^b Institute of Molecular Biosciences, University of Graz, Humboldstrasse 50, 8010 Graz, Austria

^c Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester M1 7DN, UK

^d Institute of Biotechnology and Biochemical Engineering, Graz University of Technology, Petersgasse 12, 8010 Graz, Austria

^e Austrian Centre of Industrial Biotechnology (ACIB), Petersgasse 14, 8010 Graz, Austria

Abstract

The utilization of gaseous carbon dioxide instead of bicarbonate would greatly facilitate process development for enzyme catalyzed carboxylations on a large scale. As a proof-of-concept, 1,3-dihydroxybenzene (resorcinol) was carboxylated in the ortho-position using pressurized CO₂ (∼30–40 bar) catalyzed by ortho-benzoic acid decarboxylases with up to 68% conversion. Optimization studies revealed tight pH-control and enzyme stability as the most important determinants.


Fig. 1 (a) Enzyme-catalyzed de/carboxylation of resorcinol (1). Carboxylated product 2 is a mixture of regio-isomeric 2,6- (2,6-dhba, 2a) and 2,4-dihydroxybenzoic acid (2,4-dhba, 2b) with a ratio of 3:4;^10b (b) CO₂ pressure dependence of the carboxylation of 1 using 2,3-DHBD_Ao; (c) carboxylation activity of decarboxylases with CO₂ (30 bar) using 1 as a substrate; (d) stopped-flow measurements of the decarboxylation of 2,6-dhba (2a) with pressure-pretreated (≤1.5 kbar) 2,3-DHBD_Ao and 2,6-DHBD_Rs.

Conclusion

In summary, we have demonstrated that pressurized carbon dioxide can be used directly as a carboxylating agent in the enzyme catalyzed o-carboxylation of a phenol as an alternative to the high concentration of bicarbonate. Two enzyme candidates (2,3-DHBD_Ao and SAD_Tm) readily accepted the alternative CO₂ source for the carboxylation of the model substrate resorcinol. In contrast, 2,6-DHBD_Rs was inapplicable under CO₂ pressure due to irreversible inactivation, which was correlated to a decrease in pH caused by the dissociation of H₂CO₃.

Overall, the use of pressurized CO₂ gas significantly improves the efficiency of biocatalytic carboxylations and facilitates downstream-processing of this benign and sustainable approach in using CO₂ as a carbon feedstock for the synthesis of organic acids.

Katharina Plasch

DOCTORAL STUDENT,

Katharina Plasch

tel: +43-316-380-8646
e-mail:katharina.plasch(at)uni-graz.at

Katharina Plasch

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Kurt Faber
Institute of Chemistry – Organic & Bioorganic Chemistry
Karl Franzens Universität Graz
Heinrichstrasse 28
8010 Graz

e-Mail: kurt.faber@uni-graz.at
phone: +43 316 380 5332
fax: +43 316 380 9840
web: http://biocatalysis.uni-graz.at

Kurt Faber, born 1953 in Klagenfurt (Carinthia/Austria), studied chemistry at the University of Graz, where he received his PhD in 1982. After a post-doctoral fellowship from 1982 to 1983 in St. John’s (Canada) he continued his career at the University of Technology in Graz, where he became associate professor in 1997. The following year he was appointed full professor at the University of Graz, where he since heads a research group devoted to the use of biocatalysts for the transformation of non-natural compounds. He was a visiting scientist at University of Tokyo (1987/1988), Exeter University (1990), University of Trondheim (1994), Stockholm University (2001) and University of Minnesota (2005).

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Silvia M. Glueck

Silvia M. Glueck, born 1973 in Bruck/Mur (Austria), studied Chemistry at the University of Graz, where she received her PhD under the supervision of Prof. K. Faber in 2004. From 2005 to 2006 she worked as a post-doctoral fellow with Prof. N. J. Turner at the University of Edinburgh and the University of Manchester (MIB). In 2007 she returned to the University of Graz to join Prof. W. Kroutil, and in 2008 she became Research Scientist at the Research Centre Applied Biocatalysis in the group of Prof. K. Faber. Her research interests are focusing on biocatalysis, molecular biology and organic synthesis.

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Pressurized CO₂ as a carboxylating agent for the biocatalytic ortho-carboxylation of resorcinol

K. Plasch, G. Hofer, W. Keller, S. Hay, D. J. Heyes, A. Dennig, S. M. Glueck and K. Faber, Green Chem., 2018, 20, 1754

DOI: 10.1039/C8GC00008E

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