Novel Benzopyridothiadiazepines as Potential Active Antitumor Agents

Abstract

The synthesis of novel thiadiazepine derivatives, that could be considered as constraint analogues of E-7010, are reported. These molecules were evaluated for their antiproliferative activity toward the murine L1210 leukemia cell line. Flow cytometric studies performed on L1210 cells with the most cytotoxic compounds showed an accumulation of the cells in the G2/M phases of the cell cycle with a significant percentage of tetraploid cells (8N DNA content). Submicromolar cytotoxicities were observed with compounds 2b, 4b, 4e, 4g, and 4i. Two of them, compounds 2b and 4b, were found to be potent inhibitors of tubulin polymerization with IC50 of respectively 3.8 and 2.4 microM compared to 2.4 microM for desoxypodophyllotoxin. A 4-methoxyphenylethyl substitution on the pyridinyl nitrogen of the benzopyridothiadiazepine was found to be essential for the antiproliferative activity. The in vitro activities of compounds 2b and 4b make benzopyridothiadiazepine dioxides a promising new class of tubulin binders which warrant further in vivo evaluation.

A summary of seven- and eight-membered ring sultam syntheses via three Michael addition reactions

“…The mixture was extracted by CH 2 Cl 2 , the organic layer was dried over MgSO 4 , concentrated, and purified by flash chromatography to afford seven-and eight-membered ring -N,O-sultam 6a-g. Chlorobenzyl)-1,3,4,5a,6,10b-hexahydroindeno [1,2-f] [1,4,5] Allyl-1,3,4,6-tetrahydrobenzo[f] [1,4,5] General procedure for producing eight-membered ring -N,N-sultams 9a-g 8a (0.20 g, 0.98 mmol) was added to a dried flask, followed by the addition of CH 3 OH (2 mL) and iso-propylamine (0.09 g, 1.50 mmol). Then the mixture was refluxed for about 5 h (monitored by TLC analysis).…”

“…Substantial time and effort have been expended to develop quick and effective synthetic methods of sulfonamides and their cyclic analogs. Sulfonamides have attracted a lot of attention due to their extensive chemical and biological activities [1][2][3][4][5][6][7][8][9][10]. Six sulfonamide derivatives displaying a range of potent biological activities are shown in Fig.…”

Synthesis of Aromatase Inhibitors and Dual Aromatase Steroid Sulfatase Inhibitors by Linking an Arylsulfamate Motif to 4‐(4H‐1,2,4‐triazol‐4‐ylamino)benzonitrile: SAR, Crystal Structures, in vitro and in vivo Activities

“…For the ethylene linker series 4-(2-hydroxyethyl)phenol (9) was benzyl-protected to give 16 a (R 1 = H, R 2 = Bn). [30] The fluoro and chloro analogues 16 b (R 1 = F, R 2 = Bn) and 16 c (R 1 = Cl, R 2 = Bn) were obtained from the corresponding 2-halo-4-hydroxyphenylacetic acids 10 and 11 in two steps by benzyl protection of the aromatic hydroxy group and reduction of the phenylacetic acids 13 [31] and 14 [32] with LiAlH 4 . The protection of the phenolic hydroxy group as benzyl ether has previously been found unsatisfactory for the bromo derivatives because of the variable degrees of debromination observed during the subsequent deprotection step using palladium-catalysed hydrogenation.…”

Parallel synthesis of structurally diverse aminobenzimidazole tethered sultams and benzothiazepinones

“…Sultams or cyclic sulfonamides are useful structural motifs in heterocyclic synthesis, 4 applied as chiral auxiliaries in asymmetric synthesis, 10 and are actively sought in the areas of antimalarial, 11 antiviral, 12 anticancer, 13 antimicrobial, 14 and antileukemic research. 15,16 Likewise, aminobenzimidazole is a recurring template in the design and for the development of combinatorial libraries of drugs and drug-like molecules. 17,18 …”