DNA-Directed Alkylating Agents. 6. Synthesis and Antitumor Activity of DNA Minor Groove-Targeted Aniline Mustard Analogs of Pibenzimol (Hoechst 33258)

Abstract

A series of nitrogen mustard analogues of the DNA minor groove binding fluorophore pibenzimol (Hoechst 33258) have been synthesized and evaluated for antitumor activity. Conventional construction of the bisbenzimidazole ring system from the piperazinyl terminus, via two consecutive Pinner-type reactions, gave low yields of products contaminated with the 2-methyl analogue which proved difficult to separate. An alternative synthesis was developed, involving construction of the bisbenzimidazole from the mustard terminus, via Cu(2+)-promoted oxidative coupling of the mustard aldehydes with 3,4-diaminobenzonitrile to form the monobenzimidazoles, followed by a Pinner-type reaction and condensation with 4-(1-methyl-4-piperazinyl)-o-phenylenediamine. This process gives higher yields and pure products. The mustard analogues showed high hypersensitivity factors (IC50AA8/IC50 UV4), typical of DNA alkylating agents. There was a large increase in cytotoxicity (85-fold) across the homologous series which cannot be explained entirely by changes in mustard reactivity and may be related to altering orientation of the mustard with respect to the DNA resulting in different patterns of alkylation. Pibenzimol itself (which has been evaluated clinically as an anticancer drug) was inactive against P388 in vivo using a single-dose protocol, but the short-chain mustard homologues were highly effective, eliciting a proportion of long-term survivors.

Trimethylsilyl Chloride Catalyzed Synthesis of Substituted Benzimidazoles Using Two Phase System Under Microwave Conditions, and Their Antimicrobial Studies

“…General. 1 H NMR spectra were recorded on a Bruker 300-MHz spectrometer in the solvent indicated with TMS as the internal standard. All chemical shifts are given in ppm and the coupling constants are given in Hz.…”

“…Compounds that exhibit the functionality of benzimidazoles have been used in the area of pharmaceuticals [1][2][3][4][5] . These high profile applications of compounds with benzimidazoles structures have prompted extensive studies for their synthesis.…”

Synthesis and evaluation of antibacterial activity for a series of N-phthaloylglycine derivatives

“…Benzimidazole derivatives are very useful intermediates of pharmaceutically important compounds [8]. They are applicable as antiulcer, antihypertensive, antifungal, antiviral, antihistamine, antimicrobial, antiallergic, antioxidant, antitubercular, and in-vitro anti-HIV-1 [9].…”

Highly Efficient and Facile Method for Synthesis of 2-Substituted Benzimidazoles via Reductive Cyclization of O-Nitroaniline and Aryl Aldehydes

“…Substituted benzimidazole derivatives have found applications in diverse therapeutic areas including antihypertensives, antivirals, antifungals, anticancers, and antihistaminics [1]. There are two general methods for the synthesis of 2-substituted benzimidazole.…”