Synthesis of novel perillyl-dihydropyrimidinone hybrids designed for antiproliferative activity

Abstract

A series of fifteen novel dihydropyrimidinone hybrid compounds were synthesized in good yields via a multicomponent reaction combined with the Huisgen reaction. The antiproliferative activity was investigated against nine tumor cell lines, and four hybrid compounds (TGI < 10 μM) showed promising antiproliferative activity against the tumor cell lines OVCAR-3 (ovarian), UACC-62 (melanoma) and U251 (glioma). Several hybrid compounds assayed have high TGI values (TGI 147.92-507.82) for the human keratinocyte cell line (HaCat), which reveals selectivity to cancer cells.

Fig. 1. Picture definition of hybrid drugs and chimera drugs.

Fig. 2. Biologically active hybrid compounds.

Fig. 3. Antiproliferative dihydropyrimidinones.

Fig. 4. Hybrid compounds from perillyl alcohol.

Fig. 5. Strategy to hybridize DHPMs and perillyl alcohol via a 1,2,3-triazolyl linker.

Scheme 1. Synthesis of propargyloxy dihydropyrimidinones.

Scheme 2. Synthesis of perillyl azide and the Cu(i)-catalyzed Huisgen reaction.

Fig. 6. The most potent perillyl–dihydropyrimidinone hybrids.

Fig. 7. Profile of monastrol against different tumor cell lines.

Fig. 8. Profile of oxo-monastrol against different tumor cell lines.

Fig. 9. Profile of hybrid 8b against different tumor cell lines.