Molecular modeling, design, and synthesis of some potential selective DNA minor groove alkylators

Abstract

Small molecules-DNA interactions are responsible for many biological processes. The DNA present in normal and tumor cells are almost identical. Therefore, DNA targeting drugs are used only in serious and life-threatening conditions such as cancer. DNA alkylators represent the majority of antineoplastic drugs that are covalently attached to DNA and inhibit its replication. The lack of selectivity and targetability for the DNA of cancer cells resulted in severe adverse effects, such as bone marrow depression, hair loss, general weakness, and many other immense side effects. The discovery and the structure elucidation of the cyclopropylpyrroloindole (CPI) class of compounds that comprises duocarmycin SA and (+)-CC-1065 have attracted interest towards the generation of these compounds and many other structural analogs due to their immense potency and novel mechanism of action as DNA minor groove alkylators within AT rich regions. Similarly, anthramycin and its analogs of the pyrrolobenzodiazepine (PBD) class of compounds alkylate DNA in the minor groove but within the GC rich regions. Moreover, the drug hybridization approach represents an attractive opportunity in designing such dual inhibitors, which are capable of specifically targeting certain regions in the DNA, via more than one mode of action as a means of avoiding the multidrug resistance problem linked to many chemotherapeutic drugs. Recently, increased research efforts have been focused in the design and synthesis of hybrid anticancer compounds that are effective and safe; however, limited attention has been devoted to combining the structural features of both the CPI and PBD classes in one compound as possible DNA sequence specific cross linkers. The current study addresses three synthetic pathways were designed. The first includes coupling the 4-(benzyloxy)-1-hydroxy-2-naphthoic acid 75 with the aniline analog 76. The second approach involves the coupling the triflate derivative 91 with the tin methyl acetate derivative 97. Additionally, the rational drug design and synthesis of compounds that possess a blending of CPI and PBD structural scaffolds, with some DNA sequence specific targeting moieties such as lexitropsins and Dervan polypeptides. The initial target compounds were identified as 2-phenyl-1,2,10,10a-tetrahydrobenzo[f]cyclopropa[d]isoquinoline-3,5-dione 38 and methyl 1-methyl-4-((5-oxo-3,5,10,10a-tetrahydrobenzo[f]cyclopropa[d]isoquinolin-2(1H)-yl)methyl)-1H-pyrrole-2 carboxylate 39 that were synthesized through an imine-anhydride condensation reaction as a key step to construct the benzoisoquinoline scaffold followed by reduction of the carboxylic acid functionality, debenzylation under catalytic hydrogenolysis conditions and finally Winstein spirocyclization utilizing sodium hydride.