Synthesis and biological activity of fused tetracyclic Pyrrolo[2,1-c][1,4]benzodiazepines

Abstract

Cancer remains the second major cause of death in the world. Thus, there is a pressing need to identify potential synthetic route for the development of novel anticancer agents which will serve as lead compounds to effectively combat this life-threatening epidemic. Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) have sparked a great interest as lead compounds because of their cancerostatic and anti-infective properties. The twisted molecular structure of PBD analogs provides both helical and chiral elements. In an effort to expand novel PBDs that interact with the key exocyclic amino group of the DNA-guanine base, we hypothesized that construction of a fused cyclic active system, would likely serve as an electrophilic site when compared to traditional electrophilic C11-N10 imine group. To examine our theory, we report herein the synthesis and cell viability/cytotoxicity of a series of PBD analogs using NCI-60 cell lines screening. Thus, compounds 1-13 were synthesized and fully characterized. The selected PBDs were found to have marginal inhibition of growth, up to 30%, for certain cell lines.

Keywords: Organic chemistry; Pharmaceutical chemistry.

Fig. 1

Naturally occurring PBDs and their synthetic analogs.

Fig. 2

Reagents and conditions: (a) DMF, 155 °C, 5h, 82.0%; (b) Lawesson's reagent, THF, rt, 15h, 87.0%; (c) n-propylamine, HgCl₂, rx, 1h, 88%; (d) bis(2,4,6-trichlorophenyl)-2-phenylmalonate, 190 °C, 10 min, 75%; (e) NH₃(g)(anhy.), HgCl₂, THF, rx, 1h, 86% (f) bis(2,4,6-trichlorophenyl)-2-phenylmalonate, 170–180 °C, 10 min, 63%; (g) N₂H₄.H₂O (98%), EtOH(abs.), rt, 15h, 99.0%; (h) CDI, dioxane (anhy.), reflux, 24h, 99.0%; (i) TDI, dioxane (anhy.), rx, 24h, 80.0%; (j) NH₂OH.HCl, K₂CO₃, ethanol, rt, 24h, 82%; (k) CDI, dioxane, rx, 12h, 88%/TDI, dioxane, rx, 12h, 90%; (l) α-bromoacetyl chloride, THF, rt, under N₂(g), 15h, 75%. CDI: 1,1′-carbonyldiimidazole, TDI: 1,1′-thiocarbonyldiimidazole.

Fig. 3

In vitro cytotoxicity assay of PBD analogs from MTT Assay.