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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc 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 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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4H-1-Benzopyran-4-one, 2-[2-(2,6-dichlorophenyl)ethenyl]-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-

Molecular Weight






CSIR-IIIM Jammu has filed an IND Application of “IIIM-290” to Drug Controller General of India for conducting Phase I/Phase II clinical trial of its capsule formulation in patients with locally advanced or metastatic pancreatic cancer. This IND candidate has emerged from the eight years of medicinal chemistry/ preclinical efforts of IIIM Jammu in the area of small molecule kinase inhibitors. IIIM-290 (NCE) is an orally bioavailable CDK inhibitor, obtained via semisynthetic modification of a natural product rohitukine. Institute has already secured a patent on this small molecule as well as on its oral capsule formulation.

IIIM-290 is a potent and oral CDK inhibitor with IC50s of 90 and 94 nM for CDK2/A and CDK9/T1.

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Discovery and Preclinical Development of IIIM-290, an Orally Active Potent Cyclin-Dependent Kinase Inhibitor

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Cite this: J. Med. Chem. 2018, 61, 4, 1664-1687


Abstract Image

Rohitukine (1), a chromone alkaloid isolated from Indian medicinal plant Dysoxylum binectariferum, has inspired the discovery of flavopiridol and riviciclib, both of which are bioavailable only via intravenous route. With the objective to address the oral bioavailability issue of this scaffold, four series of rohitukine derivatives were prepared and screened for Cdk inhibition and cellular antiproliferative activity. The 2,6-dichloro-styryl derivative IIIM-290 (11d) showed strong inhibition of Cdk-9/T1 (IC50 1.9 nM) kinase and Molt-4/MIAPaCa-2 cell growth (GI50 < 1.0 μM) and was found to be highly selective for cancer cells over normal fibroblast cells. It inhibited the cell growth of MIAPaCa-2 cells via caspase-dependent apoptosis. It achieved 71% oral bioavailability with in vivo efficacy in pancreatic, colon, and leukemia xenografts at 50 mg/kg, po. It did not have CYP/efflux-pump liability, was not mutagenic/genotoxic or cardiotoxic, and was metabolically stable. The preclinical data presented herein indicates the potential of 11d for advancement in clinical studies.




InventorRam A. VishwakarmaSandip B. BharateShashi BhushanDilip M. MondheShreyans K. JainSamdarshi MeenaSantosh K. GuruAnup S. PathaniaSuresh KumarAkanksha BehlMubashir J. MintooSonali S. BharatePrashant Joshi Current Assignee Council of Scientific and Industrial Research (CSIR)

The disruption of any internal and external regulation of cellular growth leads to tumorogenesis by uncontrolled proliferation. This loss of control occurs at multiple levels in most of the cancer cases. Cyclin-dependent kinases (CDKs) have been recognized as key regulators of cell cycle progression. Alteration and deregulation of CDK activity have pathogenic link to the cancer. Number of cancers are associated with hyper-activation of CDKs as a result of mutation of the CDK genes or CDK inhibitor genes. Therefore, CDK inhibitors or modulators are of great interest to explore as novel therapeutic agents against cancer (Senderowicz, A. M. Leukemia 2001, 15, 1). Several classes of chemical inhibitors of CDK activity have been described (Zhang, J. et. al. Nat Rev Cancer. 2009, 9, 28) and some of them have reached to clinical pipeline for cancer.

Because CDK inhibitors are ATP competitive ligands; hence earlier they were typically described as purine class of compounds for example dimethylaminopurine, a first substance to be known as a CDK inhibitor (Neant, I. et al. Exp. Cell Res. 1988, 176, 68), olomoucine (Vesely, J. et al. Eur. J. Biochem. 1994, 224, 771) and roscovitine (Meijer, L. et al. Eur. J. Biochem. 1997, 243, 527). The IC50values of these purine class of compounds for CDK1/cyclin B are 120, 7 and 0.2-0.8 μM respectively (Gray, N. et al. Curr. Med. Chem. 1999, 6, 859). Some of the more potent members of this series have been prepared by the Schultz group using combinatorial approaches (Gray, N. S. et al. Science 1998, 281, 533). Number of synthetic flavoalkaloids having potent CDK inhibitory activity has been reviewed recently (Jain, S. K. et al. MiniRev. Med. Chem. 2012, 12, 632).

Specific CDKs operate in distinct phases of the cell cycle. CDK complexes with their respective type cyclin partners such as, complex of CDK2 and cyclin A is responsible for the cell’s progression from G1 phase to S phase (Sherr, C. J. Science 1996, 274, 1672). DNA synthesis (S phase) begins with the CDK mediated phosphorylation of Rb (retinoblastoma) protein. Phosphorylated Rb is released from its complex with E2F. The released E2F then promotes the transcription of numerous genes required for the cell to progress through S phase, including thymidylate synthase and dihydrofolate reductase which are required for cell progression (Hatakeyama, M. et. al, Cell Cycle Res. 1995, 1, 9; Zhang, H. S. et. al. Cell 1999, 97, 53). Majority of human cancers have abnormalities in some component of the Rb pathway because of hyper-activation of CDKs resulting from the over-expression of positive cofactors (cyclins/CDKs) or a decrease in negative factors (endogenous CDK inhibitors) or Rb gene mutations (Sausville, E. A. et. al, Pharmacol. Ther. 1999, 82, 285).

The CDK-9 is a member of the Cdc2-like family of kinases. Its cyclin partners are members of the family of cyclin T (T1, T2a and T2b) and cyclin K. The CDK-9/cyclin T complexes appear to be involved in regulating several physiological processes. CDK9/cyclin T1 belongs to the P-TEFb complex, and is responsible for the phosphorylation of carboxyl terminal domain of the RNA Polymerase II, thus promoting general elongation. CDK-9 has also been described as the kinase of the TAK complex, which is homologous to the P-TEFb complex and is involved in HIV replication. CDK9 also appears to be involved in the differentiation program of several cell types, such as muscle cells, monocytes and neurons, suggesting that it may have a function in controlling specific differentiative pathways. In addition, CDK-9 seems to have an anti-apoptotic function in monocytes, that may be related to its control over differentiation of monocytes. This suggests the involvement of CDK-9 in several physiological processes in the cell, the deregulation of which may be related to the genesis of transforming events that may in turn lead to the onset of cancer. In addition, since the complex CDK-9/cyclin T1 is able to bind to the HIV-1 product Tat, the study of the functions of CDK-9/cyclin T may be of interest in understanding the basal mechanisms that regulate HIV replication (Falco, G. D. and Giordano A. Cancer Biol. Therapy 2002, 1, 337).

Rohitukine belongs to a class of chromone alkaloids and it was isolated by chemists at Hoechst India Ltd. in the early 1990’s from Dysoxylum binectariferum Hook. which is phylogenetically related to the Ayurvedic plant, D. malabaricum Bedd., used for rheumatoid arthritis. Rohitukine was isolated as the constituent responsible for anti-inflammatory and immunomodulatory activity (Naik, R. G. et. al. Tetrahedron 1988, 44, 2081; U.S. Pat. No. 4,900,727, 1990). Medicinal chemistry efforts around this nature-derived flavone alkaloid led to discovery of two promising clinical candidates for treatment of cancer viz. flavopiridol of Sanofi-Aventis and P-276-00 of Piramal life sciences. Recently FDA has granted the orphan drug status to flavopiridol for treatment of chronic lymphocytic leukemia (CLL).

The molecular formula of rohitukine is C16H19NOand the structure has a molecular weight of 305.32 g/mol. The chemical structure of rohitukine (1) is shown below. The present invention reports new semi-synthetic analogs of rohitukine as promising inhibitors of cyclin-dependent kinases such as CDK-2 and CDK-9.

Figure US09932327-20180403-C00002

Synthesis of styryl analog 2-(2,6-dichlorostyryl)-5,7-dihydroxy-8-(3-hydroxy-1-methylpiperidin-4-yl)-4H-chromen-4-one (33)

This compound was synthesized using the procedure as described in example 4. Yellow solid; 1H NMR (DMSO-d6, 400 MHz): δ 7.68 (m, 2H), 7.61 (d, J=16 Hz, 1H), 7.49 (t, J=8 Hz, 1H), 7.14 (d, J=16 Hz, 1H), 6.41 (s, 1H), 5.85 (s, 1H), 4.53 (brs, 1H), 3.10-2.50 (m, 6H of piperidine), 2.65 (s, 3H), 1.62 (m, 1H); 13C NMR (DMSO-d6, 125 MHz): δ 179.68. 171.27, 159.20, 158.02, 154.03, 133.12, 131.49, 129.75, 128.35 (2C), 128.20, 127.90, 108.81, 106.79, 100.88, 100.52, 66.35, 59.82, 54.45, 43.15, 35.79, 22.01, 20.33, ESI-MS: m/z 462.01 [M+H]+; IR (CHCl3): νmax 3400, 2921, 1652, 1577, 1550, 1417, 1380, 1191, 1085 cm−1.

///////////IIIM-290, nda, india, phase 1, dcgi, CSIR, ROHITUKINE

[1]. Bharate SB, et al. Discovery and Preclinical Development of IIIM-290, an Orally Active Potent Cyclin-Dependent Kinase Inhibitor. J Med Chem. 2018 Feb 22;61(4):1664-1687.


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




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

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
Copyright © 2018 American Chemical Society
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 !

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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).


CSIR, INDIA-WO PATENT–synthesis of amprenavir and saquinavir



A process for synthesis of syn azido epoxide and its use as intermediate in the synthesis of amprenavir and saquinavir
Published as ———WO-2013105118
Council of Scientific & Industrial Research


Gadakh, Sunita, Khanderao; Rekula, Reddy, Santhosh; Sudalai, Arumugam
Publication date 18-JUL-2013

HIV protease inhibitor

Disclosed herein is a novel route of synthesis of syn azide epoxide of formu 5, which is used as a common intermdeiate for asymmetric synthesis of HIV protease inhibitors such as Amprenavir, Fosamprenavir, Saquinavir and formal synthesis of Darunavir and Palinavir obtained by Cobalt- catalyzed hydrolyti kinetic resolution of racemic anti-(2SR, 3SR) – 3 -azido – 4 -phenyl – 1, 2- epoxybutane (azido-epoxide

IN2012DE82 10-JAN-2012 [priority]
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