An evaluation of Minor Groove Binders as anti-fungal and anti-mycobacterial therapeutics

Abstract

This study details the synthesis and biological evaluation of a collection of 19 structurally related Minor Groove Binders (MGBs), derived from the natural product distamycin, which were designed to probe antifungal and antimycobacterial activity. From this initial set, we report several MGBs that are worth more detailed investigation and optimisation. MGB-4, MGB-317 and MGB-325 have promising MICs of 2, 4 and 0.25 μg/mL, respectively, against the fungus C. neoformans.MGB-353 and MGB-354 have MICs of 3.1 μM against the mycobacterium M. tuberculosis. The selectivity and activity of these compounds is related to their physicochemical properties and the cell wall/membrane characteristics of the infective agents.

Selective in vitro anti-cancer activity of non-alkylating minor groove binders

“…6 Furthermore, replacement of the alkene link with an amidine resulted in significantly active compounds against the fungus Cryptococcus neoformans only. 9 The data shows that there is a significant effect on activity due to changing one of the heterocyclic subunits from a pyrrole to a much more lipophilic isopentylthiazole. Specifically, S-MGBs 4, 74 and 317, our three identified lead compounds ( these six compounds.…”

“…The protocols used were similar to those in our previous work, with the synthesis for the novel compounds described below. 9 To prepare compounds with a pyrrole-amidine or pyrrole-amide linked head group, the appropriate nitro dimer was reduced to the corresponding amine by hydrogenation with palladium on carbon as a catalyst in methanol at room temperature. The amine was then reacted with 1-methyl-4-nitro-1Hpyrrole-2-carbonyl chloride (prepared by refluxing the corresponding carboxylic acid in thionyl chloride) in the presence of triethylamine at room temperature.…”

“…Our team has developed several potent anti-infective compounds, selectively targeting various infectious organisms such as bacteria, 7 parasites, 8 and fungi. 9 This includes the discovery of the drug MGB-BP-3 which, in collaboration with MGB Biopharma, is about to progress into phase II clinical trials for the treatment of Clostridium difficile infections. In this study, a panel of our distamycin-based S-MGBs are investigated for potential cytotoxic activity towards different cancer cells and whether they show selectivity towards cancer cells compared to non-cancer cells.…”

An overview of recent advances in duplex DNA recognition by small molecules

“…This has been attributed to strong self-association (dimerization) in an antiparallel, head-to-tail orientation in aqueous solution during complex formation with duplex DNA oligomers verified via NOE experiments [ 61 ]. They further reported several structurally diverse MGBs, derived from distamycin, in order to probe their antifungal and antimycobacterial activity; several of these novel conjugates showed promising activity against the fungus C. neoformans (MIC 80 s ranging from 0.25–4 μg/mL) and the mycobacterium M. tuberculosis (MIC 99 s 3.1 μM) [ 62 ].…”

First Structure of a Designed Minor Groove Binding Heterocyclic Cation that Specifically Recognizes Mixed DNA Base Pair Sequences

“…[3][4][5] Though these compoundsh ave been quite successful in modulating specific biological functions, they are also quite limited for many applications by their lack of diversity in the sequence-specific DNA recognition. [6,7] As one approacht ow iden the sequencer ecognition of these compounds, we have introduced H-bond accepting modules to A·T recognizing groups to explore G·C (bp) recognition in the context of heterocyclic cations tructures. [8][9][10] The first step in this process, addingaH-bond accepting module for recognition of aG ·C bp with flankingA ·T bps, has been successfully accomplished with severalq uite different, new compound designs.…”