DNA minor groove binders as potential antitumor and antimicrobial agents

Abstract

DNA minor groove binders constitute an important class of derivatives in anticancer therapy. Some of these compounds form noncovalent complexes with DNA (e.g., distamycin A, Hoechst 33258, and pentamidine) while others DNA-binding compounds (such as CC-1065) cause cleavages in the DNA backbone. In this article, we have reviewed the minor groove binders currently in preclinical evaluation in the last years. Diarylamidines such as DAPI, berenil, and pentamidine; bis-benzimidazoles such as Hoechst 33258; ecteinascidins, pyrrololo [2,1-c]-[1,4]-benzodiazepines (PBDs), CC-1065, and distamycins are the classes discussed in this review article. A special section has been dedicated to hybrid molecules resulted by the combination of two minor groove binders, especially for derivatives of naturally occurring antitumor agents, such as anthramycin or the alkylating unit of the antibiotic CC-1065, and distamycin frames.

Traditional Chinese Medicine Active Ingredient-Metal Based Anticancer Agents

“…DNA replication in tumour cells will be blocked by the small molecule intercalation of the neighboring base pairs of DNA. On the other hand, topoisomerases are ubiquitous molecules that relieve the torsional stress in the DNA helix generated as a result of replication, transcription, and other nuclear processes; they are also specific targets for a number of anticancer agents (Baraldi et al, 2004), including the camptothecins, indolocarbazoles, and indenoisoquinolines. These compounds bind to a transient topoisomerase I (TOPO I)-DNA covalent complex and inhibit the resealing of a single-starnd nick that the enzyme creates to relieve superhelical tension in duplex DNA (Holfalnd et al, 2000;Staker et al, 2005).…”

Evaluation of a reductively activated duocarmycin prodrug against murine and human solid cancers

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Mechanistically, this selective DNA alkylation is achieved through the forced adoption of a helical conformation upon binding to the minor-groove AT-rich regions of DNA, which disrupts the stabilizing vinylogous amide and activates the cyclopropane for nucleophilic attack. 19,20 These natural products are not clinically viable due to either severe adverse events, including lethal hepatotoxicity and extreme myelotoxicity, or a lack of in vivo activity.…”

“…19,20 These natural products are not clinically viable due to either severe adverse events, including lethal hepatotoxicity and extreme myelotoxicity, or a lack of in vivo activity. 1,21,22 As a result of the high systemic toxicity and reduced selectivity of this class of compounds, a new strategy has emerged to develop prodrugs that selectively release the free drug in the tumor. This strategy, known as in situ activation, seeks to design systems where an intrinsically reactive species is formed from a comparatively stable precursor at or near the site of action, thereby selectively activating a compound in the presence of its molecular target.…”

Synthesis, DNA Interactions and Anticancer Evaluation of Novel Diamidine Derivatives of 3,4-Ethylenedioxythiophene

“…Despite this new information, DNAtargeted chemotherapy of cancer is still largely based on the application of drugs that have been in use for some time. [3][4][5] Among different structures, notable attention has been given to rational design, synthesis and characterisation of the structure-activity relationship of diarylamidines, small molecules that bind through noncovalent interaction to the minor groove of B-DNA. [6][7][8] Diarylamidines have a wide range of potential therapeutic applications, such as ACIS inhibitors, 9 antiparasitic, 10,11 antifungal, 12 antibacterial, 13,14 antiviral 15 and anticancer agents.…”