The development of bis(hydroxymethyl)pyrrole analogs as bifunctional DNA cross-linking agents and their chemotherapeutic potential

Abstract

Bifunctional DNA cross-linking agents are widely used as chemotherapeutic agents in clinics. The advance in the development of these agents as potential antitumor agents has generated various types of bis(hydroxymethyl)pyrrole analogs. In order to develop highly effective anticancer agents, it is necessary to understand the chemophysical properties, structure-activity relationships, therapeutic potency, toxicity/safety, and pharmacokinetics of these DNA cross-linking agents. This review presents an overview of the recent advances in developing various types of bis(hydroxymethyl)pyrrole analogs with potential antitumor activity to provide more information for future drug design and strategies for combination chemotherapy. The rational drug design, chemical syntheses, antitumor activity, mechanism of action, and development of combined chemotherapy regimens, including a DNA repair inhibitor, are discussed.

Keywords: (2,3-dihydro-5-(3′,4′-dichlorophenyl)-6,7-bis(hydroxymethyl)-1H-pyrrolizine bis(iso-propylcarbamate); ATO; Antitumor agents; Bifunctional DNA cross-linking agents; Bis(hydroxymethyl)pyrroles; CR; Cytotoxicity; DHP; DMAD; DNA double-strand break; DNA-PK; DNA-dependent protein kinase; DSB; EGFR; Hybrid pharmacophore; IP inj.; IPP; IV inj.; Indolizino[6,7-b]indole; MDR; MMC; MTD; P-glycoprotein; P-gp; PARP; SARs; arsenic trioxide; complete tumor remission; dihydropyrrolizine alcohol; dimethyl acetylenedicarboxylate; epidermal growth factor receptor; intraperitoneal injection; intravenous injection; maximum tolerated dose; mitomycin C; multidrug-resistant; poly ADP-ribose polymerase; structure–activity relationships; topo I; topo II; topoisomerase I; topoisomerase II.