Considerations concerning design and mechanism of action of a new class of anticancer dual DNA intercalators

Summary 

Cancer is one of the most serious and merciless health problems of the mankind, about seven million people dying of cancer every year. Two of the most important and promising targets in cancer chemotherapy include DNA alkylating agents and DNA intercalators. The emphasis of this work was to design, synthetize and formulate a mechanism of action for a new class of dual DNA intercalators. The dual DNA intercalators have three main parts: an alkylating unit (represented by two halo-alkyl-ester chains), an intercalator unit (five- or six-membered ring nitrogen heterocycle) and an acetophenone skeleton linker. As mechanism of action, we consider that these compounds act as dual DNA intercalators, the alkylating unit realizing a covalent bonding via DNA protein “cross-linking effect” while nitrogen heterocycles will realize noncovalent bonding via DNA intercalation with purine and pyrimidine bases from DNA and the amino acids from topoisomerases enzymes. Our hypothesis was confirmed by in vitro anticancer tests against HeLa cell lines, where the newly obtained compounds demonstrated a very good activity.