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

TMC 205

6-[3-Methyl-1(E),3-butadienyl]-1H-indole-3-carboxylic acid

C14 H13 N O2

227.2585

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

Yang Gao , Sami Osman , and Kazunori Koide *

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);

13C NMR

(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.

see

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.

Tweet