Novel (S)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4]benzodiazepine-6,12(2H,11H)-dione derivatives: Selective inhibition of MV-4-11 biphenotypic B myelomonocytic leukemia cells' growth is accompanied by reactive oxygen species overproduction and apoptosis

Abstract

A series of optically pure (R)- and (S)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4]benzodiazepine-6,12(2H,11H)-dione derivatives was designed and synthesized as novel anthramycin analogues in a three-step, one-pot procedure, and tested for their antiproliferative activity on nine following cell lines: MV-4-11, UMUC-3, MDA-MB-231, MCF7, LoVo, HT-29, A-549, A2780 and BALB/3T3. The key structural features responsible for exhibition of cytotoxic effect were determined: the (S)-configuration of chiral center and the presence of hydrophobic 4-biphenyl substituent in the side chain. Introduction of bromine atom into the 8 position (8g) or substitution of dilactam ring with benzyl group (8m) further improved the activity and selectivity of investigated compounds. Among others, compound 8g exhibited selective cytotoxic effect against MV-4-11 (IC₅₀ = 8.7 μM) and HT-29 (IC₅₀ = 17.8 μM) cell lines, while 8m showed noticeable anticancer activity against MV-4-11 (IC₅₀ = 10.8 μM) and LoVo (IC₅₀ = 11.0 μM) cell lines. The cell cycle arrest in G₁/S checkpoint and apoptosis associated with overproduction of reactive oxygen species was also observed for 8e and 8m.

Keywords: Anticancer activity; Apoptosis; Biphenotypic B myelomonocytic leukemia; Reactive oxygen species overproduction; Selective inhibition; Tricyclic benzodiazepines.