Design, Synthesis and Activity of DNA Minor Groove Alkylators and 2-Methylaristeromycins

Abstract

Abstract of part I

The DNA structural differences between normal and tumor cells are almost negligible and accordingly, DNA targeting drugs are reserved for serious and life threatening diseases such as cancer. The majority of DNA targeting antineoplastic drugs are alkylators that are covalently attached to DNA to inhibit its replication causing immense adverse effects such as general weakness, hair loss, bone marrow depression and many other severe side effects owing to the lack of targetability and selectivity for the DNA of cancer cells. Since the discovery and disclosure of the structures of the cyclopropylpyrroloindole (CPI) class of compounds that comprises (+)-CC-1065 and duocarmycin SA in the late seventies of the last century, a vast amount of research has been directed towards the synthesis of these compounds and many other structural analogs due to the increased interest in their exceeding potency and unique mechanism of action as DNA minor groove alkylators within AT rich regions. In addition, Anthramycin and its analogs of the pyrrolobenzodiazepine (PBD) class of compounds represent CG selective minor groove binders. Moreover, the hybrid drug assembly strategy offers a great opportunity in designing such dual inhibitors that are capable of eliciting more than one mode of action at a specific target as a means of circumventing the multidrug resistance problem associated with many chemotherapeutic drugs. Recently, many research groups are devoting their efforts in designing and synthesizing such hybrid agents in the hope of improving cancer therapeutics, however, scant attention has been drawn to combining the structural features of both the CPI and PBD classes in one structure as possible DNA sequence specific cross linkers. This study deals mainly with the rational drug design and synthesis of compounds that possess not only a blending of CPI and PBD structural scaffolds, but also of possible attachments with some DNA sequence specific targeting moieties such as lexitropsins and Dervan polypeptides. The initial target compounds were identified as ethyl 2-(4-methoxybenzyl)-3,5-dioxo-1,2,3,5,10,10a- hexahydrobenzo[f]cyclopropa[d]isoquinoline-1-carb- oxylate 38 and ethyl 2-(2,4-dimethoxybenzyl)-3,5-dioxo-1,2,3,5,10,10a- hexahydrobenzo [f]cyclopropa[d]isoquinoline-1-carboxylate 39 that were synthesized through an imine-anhydride cycloaddition reaction as a key step to contruct the benzoisoquinoline scaffold followed by reduction of the carboxylic functionality, debenzylation and intralmoecular Mitsunobu reaction to accomplish the final Winstein spirocyclization. An additional compound that was identified as ethyl 9-methyl-5,7-dioxo-5,7,11,11a,11b,12-hexahydrobenzo[f]cyclopropa[d]pyrrolo[1,2-b]isoquinoline-10-carboxylate 40, and two synthetic pathways were designed. The first includes coupling the bromonaphthoic acid derivative 71 with the pyrroline analog 72. An alternative route involves three different approaches for utilizing the imine–anhydride cycloadditions using the tricyclic anhydride 43.

Abstract of part II

Tuberculosis (TB) is infecting more than one third of the global population and it accounts for 2 to 3 million deaths every year. For a number of years, especially between the mid-1950s and the mid-1980s of last century, there was a remarkable decline in the incidence of TB infection due to effective treatments. The re-emergence of TB took place after the widespread of HIV in 1983. TB-HIV co-infections rendered the treatment more difficult owing to the multidrug resistance (MDR). Many nucleosides have been proven to be very effective and relatively safe medications particularly in antiviral and anticancer chemotherapy. Among the interesting Mycobacterium enzymes that can be targeted for therapy by nucleosides is the purine salvage enzyme adenosine kinase (Ado Kinase), which is responsible for catalyzing the phosphorylation of adenosine to adenosine monophosphate (AMP). 2-Methyladenosine has been shown to elicit powerful inhibitory actions on the mycobaterial Adokinase, making this compound an important lead compound for designing 2-methylated nucleoside analogs as AdoKinase inhibitors. S-adenosylhomocystein hydrolase (AdoHcy hydrolase) is another interesting enzyme that can be targeted by nucleosides. AdoHcy hydrolase plays an essential role in the methyl transfer reactions during DNA replication and Mycobacterium Tuberculosis (Mtb) is the only bacterium that has a solved crystal structure, which facilitates drug design. The naturally occuring carbocyclic nucleosides; aristeromycin (Ari) and neplanocin NpcA, are two of the exceedingly potent inhibitors of AdoHcy hydrolase, and as a consequence, they exhibit significant antiviral activity. The promising exceptional potency of 2-methyladenosine as an Ado kinase inhibitor and Ari and NpcA as AdoHcy hydrolase inhibitors led to the design and synthesis of 2-methyl NpcA (27) and 2-methyl Ari (28). This combines the structural features of both classes with the intent of achieving dual functioning inhibitors of both enzymes in an attempt to circumvent the MDR problem associated with TB infections. Another NpcA analog, 2-methyl-4′-nor NpcA (29) has been designed and synthesized in such a way that retains the structural features of 27 while avoiding the toxicity associated with NpcA. Finally, to investigate the activity and correlate this with syn-anti conformations, 2,8-dimethyl-4′-nor NpcA (30) has been prepared. Compounds 27 and 29 were assessed for their anti-tuberculosis activity and they showed no significant activity compared to Rifampicin. Anti-tuberculosis testing of compounds 28 and 30 and antiviral evaluation of all compounds are forthcoming.