Synthesis and Cytotoxicity Evaluation of Maleopimaric and Dihydroquinopimaric Esters and Amides

Abstract

Objective: The increasing social significance of antitumor drugs is associated with the high prevalence of oncological diseases and determines the need to search for and create new effective drugs. This study aims to synthesize, characterize, and evaluate the cytotoxicity potential of diterpene esters and amides (I–XIII) and (XVII–XIX). Methods: The acid chloride method was used to synthesize 1-, 1,4-, and 1,4,20- derivatives of methyl dihydroquinopimarate containing furan and indoleacetyl fragments (I–V) and C²⁰-amides of dihydroquinopimaric and maleopimaric acids containing linear, heterocyclic, and aromatic amine fragments (VI–XIII). The reaction of diethyl chlorophosphite with dihydroquinopimaric alcohols proceeds in the presence of dimethylaminopyridine in pyridine to give diethoxyphosphoryl derivatives (XVII–XIX). The structures of the synthesized compounds were confirmed by mass spectrometry and one- and two-dimensional NMR spectroscopy. Primary assessment of the in vitro cytotoxic activity of 16 synthesized compounds against a panel of 60 tumor cell lines was performed. Results and Discussion: It was found that the introduction of a diethoxyphosphoryl substituent in the C¹ position of the E ring of methyl dihydroquinopimarate and of a benzylamine fragment in the C²⁰ position of maleopimaric acid resulted in the preparation of compounds that showed a pronounced cytotoxic activity. Conclusions: Diethoxyphosphoryl derivatives (XIX) and (XVII), and benzylamide (IX) were found to be cytotoxic against one, seven, and four breast cancer, leukemia, nonsmall cell lung cancer, and melanoma and prostate cancer cell lines, respectively. The highest activity was demonstrated by maleopimaric acid benzylamide (XIII), which effectively inhibited the growth of 19 cell lines of eight cancer types and had a significant cytotoxic effect against all the studied leukemia cell lines. The resulting data show that the synthesized derivatives can be recommended for in-depth study and development of a promising group of cytotoxic drugs.