Synthesis and Antiproliferative Activity of Triphenylphosphonium Derivatives of Natural Allylpolyalkoxybenzenes

Abstract

Derivatives of natural allylpolyalkoxybenzenes conjugated to triphenylphosphonium (TPP) cations by aliphatic linkers of three, six, seven, and eight atoms were synthesized to examine the role of the polyalkoxybenzene pharmacophore, TPP fragment, and linker length in antiproliferative activities. The key synthetic procedures included (i) hydroboration-oxidation of apiol, dillapiol, myristicin, and allyltetramethoxybenzene; (ii) acylation of polyalkoxybenzyl alcohols or amines; and (iii) condensation of polyalkoxybenzaldehydes followed by hydrogenation and cyclopropyl-homoallyl rearrangement. The targeted TPP conjugates as well as the starting allylbenzenes, the corresponding alkylpolyalkoxybenzenes, and the respective alkyl-TPP salts were evaluated for cytotoxicity in a panel of human cancer cell lines using MTT and Click-iT-EdU assays and in a sea urchin embryo model. The linker of three carbon atoms was identified as favorable for selective cancer cell growth inhibition. Although the propyl-TPP salt was cytotoxic at low micromolar concentrations, the introduction of a polyalkoxybenzene moiety significantly potentiated inhibition of both cell growth and de novo DNA synthesis in several human cancer cell lines, HST-116 colon cancer, A375 melanoma, PC-3 prostate cancer, and T-47D breast carcinoma cells, while it failed to produce any developmental abnormalities in the sea urchin embryos.

Figure 1

Structures of natural polyalkoxybenzenes 1a–d and 2a, TPP conjugates of selected bioactive molecules, and selected alkyl-TPP salts.

Scheme 1. Synthesis of Alkylpolyalkoxybenzenes 2–4 and TPP-Conjugated Polyalkoxyphenyl Propanes 7a–d

Scheme 2. Synthesis of Apiol–TPP Conjugates 11, 16, and 17 with Linker Lengths of 7–8 Atoms

Reagents and conditions for the synthesis of compound 8 (ref (37)) are presented in Scheme 1.

Scheme 3. Synthesis of Polyalkoxybenzene–TPP Conjugates 22 with Hex-3-ene Linkers

Reagents and conditions for the synthesis of compounds 8 (ref (37)) are presented in Scheme 1.