A New Generation of Minor-Groove-Binding—Heterocyclic Diamidines That Recognize G·C Base Pairs in an AT Sequence Context

Abstract

We review the preparation of new compounds with good solution and cell uptake properties that can selectively recognize mixed A·T and G·C bp sequences of DNA. Our underlying aim is to show that these new compounds provide important new biotechnology reagents as well as a new class of therapeutic candidates with better properties and development potential than other currently available agents. In this review, entirely different ways to recognize mixed sequences of DNA by modifying AT selective heterocyclic cations are described. To selectively recognize a G·C base pair an H-bond acceptor must be incorporated with AT recognizing groups as with netropsin. We have used pyridine, azabenzimidazole and thiophene-N-methylbenzimidazole GC recognition units in modules crafted with both rational design and empirical optimization. These modules can selectively and strongly recognize a single G·C base pair in an AT sequence context. In some cases, a relatively simple change in substituents can convert a heterocyclic module from AT to GC recognition selectivity. Synthesis and DNA interaction results for initial example lead modules are described for single G·C base pair recognition compounds. The review concludes with a description of the initial efforts to prepare larger compounds to recognize sequences of DNA with more than one G·C base pairs. The challenges and initial successes are described along with future directions.

Synthesis, crystal structure and docking studies of tetracyclic 10-iodo-1,2-dihydroisoquinolino[2,1-b][1,2,4]benzothiadiazine 12,12-dioxide and its precursors

“…Deoxyribonucleic acid (DNA) is an exceptional target for diseases that depend on the cellular division of malignant cells, microbes and/or parasites for action. Compounds that selectively bind to nucleic acids have, therefore, produced important cellular probes, chromosomal dyes and therapeutic agents (Paul et al, 2019). The ability of small molecules to interact with DNA via minor-groove binding and intercalation is also known to inhibit DNA replication and nucleic acid synthesis in vivo, thereby promoting their use as antibiotics, antibacterials, antitumour agents and mutagens (Bunkenborg et al, 2000).…”

“…Notably, many heterocyclic DNA minor-groove binders (MGBs) are providing clinically useful drugs against diverse diseases and are finding extensive uses in technology Isoquinolinobenzothiadiazine derivatives (Troschü tz & Heinemann, 1996;Kisel & Kovtunenko, 2000;Kisel et al, 2002). (Nanjunda & Wilson, 2012;Paul et al, 2019;Rahman et al, 2019). Moreover, MGBs with the tetrahydroisoquinoline ring system have been reported (D'Incalci & Galmarini, 2010;Feuerhahn et al, 2011).…”

Nonhost Disease Resistance in Pea: Chitosan’s Suggested Role in DNA Minor Groove Actions Relative to Phytoalexin-Eliciting Anti-Cancer Compounds

“…Similarly, chitosan can suppress fungal growth by interfering with DNA and RNA synthesis [ 2 ]. The DNA affinity of netropsin is primarily due to DNA at AT-rich segments causing widening of the minor groove [ 37 , 38 ], indicating that netropsin differs in action from repressors and control proteins that target the DNA major groove. The binding of chitosan to DNA slightly alters the UV monitored melting spectra of DNA in vitro [ 1 ].…”

“…Pisatin induction also occurs when pea endocarp tissue is challenged by these “anti-cancer” drugs. The analysis of their mechanism of action has been assisted by modeling the stereochemistry of drug/DNA complexes [ 37 , 38 ]. For comparison purposes, netropsin has been selected for comparing the elicitation of phytoalexin by chitosan.…”

Sustained Release of Minor-Groove-Binding Antibiotic Netropsin from Calcium-Coated Groove-Rich DNA Particles

“…Intercalators are physically intercalated into the base pair at the center of the DNA double helix, whereas minor groove binders bind by intercalating into the minor groove of the double helix [34,35]. To date, many DNA binders have been reported as specific functional molecules [36,37,38], and they include fluorescence dyes [39], anticancer drugs [40], and antibiotics [41].…”