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Total Synthesis and Biological Studies of TMC-205 and Analogues as Anticancer Agents and Activators of SV40 Promoter



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Abstract Image
TMC 205
6-[3-Methyl-1(E),3-butadienyl]-1H-indole-3-carboxylic acid
C14 H13 N O2
Mitsubishi Tanabe Pharma (Innovator) now in biological testing
TMC-205 is a natural fungal metabolite with antiproliferative activity against cancer cell lines. The light- and air-sensitivity prevented in-depth exploitation of this novel indole derivative. Herein, we report the first synthesis of TMC-205. On the basis of its reactivity with reactive oxygen species, we developed air-stable analogues of TMC-205. These analogues are 2–8-fold more cytotoxic than TMC-205 against HCT-116 colon cancer cell line. Importantly, at noncytotoxic dose levels, these analogues activated the transcription of luciferase reporter gene driven by simian virus 40 promoter (SV40). Further, these small molecules also inhibit firefly luciferase, presumably by direct interaction.
Total Synthesis and Biological Studies of TMC-205 and Analogues as Anticancer Agents and Activators of SV40 Promoter
Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/ml500025p


Synthesisof TMC-205 (1):MeOH (1.5 mL) and aqueous
NaOH (4 M, 2.5 mL) were added to a 25-mL oven-driedround-
bottomed flask containing6(20 mg, 0.080 mmol) un-der an open atmosphere at 23°C
. The resulting solution was
covered from light and stirred in an 80°Coil bath for 2.25 h. The solution was then cooled to 23°C
, and steps
subsequent to cooling were performed in a dark environment. The solution was washed with CH2Cl2
(1 mL), and
then the aqueous layer was acidified with KHSO4
(3 M, 10 mL). The aqueous layerwas ex
tracted with EtOAc(10 mL×3). The combined organic layers were dried over Na2SO4
, filtered, and concentrated under reduced
pressure using a rotary evaporator (T
water bath= 30°C) to afford 16 mg of TMC-205 (1)
as a pale yellow solid
(88% yield, >
95% purity).
Data for TMC-205 (1):
Rf= 0.24 (40% EtOAc in hexanes);
IR (film):νmax
= 3432 (broad, O-H), 2920,2851,1644 (C=O), 1528, 1451, 1349 cm-1;
1H NMR (500 MHz, 293K, CD3OD):δ
= 7.99 (d,J= 8.3 Hz, 1H, 4-H), 7.92 (s, 1H, 2-H), 7.48 (br s,1H, 7-H), 7.35 (dd,J= 8.3, 1.5 Hz, 1H, 5-H), 6.94 (d,J= 16 Hz, 1H, 10-H),
6.67 (d,J= 16 Hz, 1H, 9-H), 5.10 (br s, 1H, 12-H), 5.03 (br s, 1H, 12-H), 1.98 (s, 3H, 13-H);
(75MHz, 293 K, CD3OD):δ= 169.0, 143.7, 139.0, 134.0, 133.8, 131.3, 130.7, 127.3, 122.1, 121.3, 116.7, 111.1,
109.9, 18.8;
HRMS (EI+) calcd for C14H13NO2
[M+] 227.0946, found 227.0936.
TMC-205, a new transcriptional up-regulator of SV40 promoter produced by an undentified fungus. Fermentation, isolation, physico-chemical properties, structure determination and biological activities
J Antibiot 2001, 54(8): 628
A new transcriptional up-regulator designated TMC-205 was discovered from the fermentation broth of an unidentified fungal strain TC 1630 by using an SV40 promoter-luciferase reporter assay. Based on spectroscopic analyses, its structure was determined to be (E)-6-(3-methyl-1,3-butadienyl)- H-indole-3-carboxylic acid. Expression of the luciferase activity was activated ca. 2-, 4-, and 6-fold by 1, 10, and 100 microM TMC-205, respectively. TMC-205 activated the transcriptional activity in a manner dependent on the presence of the enhancer element of SV40 in its promoter region.

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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 AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 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, 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 32 PLUS year tenure till date Feb 2023, 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 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, 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 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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