Crystal-structure-based design and synthesis of benz[cd]indole-containing inhibitors of thymidylate synthase

Abstract

The X-ray crystal-structure-based design, synthesis, and biological activity of a novel family of benz[cd]indole-containing inhibitors of thymidylate synthase (TS) are described. The structure-activity of the lead compound was studied by conceptually dividing the molecule into four regions and independently optimizing the substituents for each region. Combination of favored substituents for each region led to inhibitors with Ki's against the human enzyme in the range of 10-20 nM. Thymidine shift experiments suggested that the cytotoxic properties of the best enzyme inhibitors were due to TS targeting in cells. The inhibitors were synthesized from substituted 6-aminobenz[cd]indol-2(1H)-ones by alkylation with both a simple alkyl group and a substituted benzylic portion. The 2,6-diaminobenz[cd]indoles were prepared from the corresponding lactams by conversion to the thiolactam, alkylation to the methylated thiolactam, and then displacement with a substituted or unsubstituted amine.

Exploring Acyclic Nucleoside Analogues as Inhibitors of Mycobacterium tuberculosis Thymidylate Kinase

“…): 266-268 8C. [28] In our hands, this compound tends to decompose and therefore was transformed into its corresponding acetamido derivative as follows. A solution containing 6-aminobenzoA C H T U N G T R E N N U N G [c,d]indol-2(1H)-one (700 mg, 3.80 mmol) in glacial acetic acid (12 mL) and acetic anhydride (4.2 mL) was stirred at reflux for 1 h. Volatiles were removed and the residue was purified by flash column chromatography (CH 2 (32).…”

“…The 6-aminobenzoA C H T U N G T R E N N U N G [c,d]indol-2(1H)-one was synthesized, as described, [28] through catalytic hydrogenation of the (29). However, as this amino compound was quite unstable in our hands, the amino derivative obtained after hydrogenation was directly transformed into its acetamide derivative (30) and was used as such in the next steps.…”

“…However, as this amino compound was quite unstable in our hands, the amino derivative obtained after hydrogenation was directly transformed into its acetamide derivative (30) and was used as such in the next steps. Thus, reaction of benzoA (28) or its 6-nitro analogue (29) [28] with (Z)-1,4-dichloro-2-butene in the presence of NaH, as described for other halides, [27,29] afford-ed the monosubstituted compounds 31 and 32 in 84 and 54 % yields, respectively. Alternatively, the 6-acetamide derivative 30 reacted with (Z)-1,4-dichloro-2-butene in the presence of NaOMe afforded 33 in 67 % yield.…”

“…NaBH 4 (378 mg, 10.0 mmol) was added in portions to a solution of 25 (377 mg, 1.0 mmol) in trifluoroacetic acid (TFA) (2 mL) at 0 8C. The reaction was allowed to reach room temperature and was further stirred for 8 h. [28] (1.0 g, 4.67 mmol) in THF (75 mL) was placed in a Parr hydrogenation bottle and 110 mg of 5 % Pd/C were added. The mixture was hydrogenated under 40 psi of H 2 for 9 h. The reaction mixture was filtered through Celite and the filtrate evaporated.…”

Characterization of receptors with a new negative image: Use in molecular docking and lead optimization

“…All the selected systems have been the target of drug design efforts; see, e.g., dhf, [41][42][43] hivp, [44][45][46][47][48] fkb, 6,49 throm, 50,51 ts, [52][53][54] trf, 55 hgh 56,57 .…”