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.

Covalent Conjugates of Allylbenzenes and Terpenoids as Antibiotics Enhancers with the Function of Prolonged Action

“…As adjuvants, in our scientific group, compounds of the terpenoid and flavonoid series are extensively studied, which show synergism with the main drug—antibiotics MF, levofloxacin, rifampicin, etc. Terpenoids and flavonoids are extracted from essential oils of plants that exhibit a number of remarkable biological effects [ 6 , 28 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ], including analgesic, antibacterial, anti–inflammatory, and antioxidant activity.…”

Triphenylphosphine Derivatives of Allylbenzenes Express Antitumor and Adjuvant Activity When Solubilized with Cyclodextrin-Based Formulations

“…In this regard, the non-toxic components of natural extracts and oils attract attention as potential adjuvants to strengthen the main drug (antibacterial or antitumor drug) and reduce the off-target effects. The individual components of essential oils (allylbenzenes [44][45][46][47], terpenoids [48,49], terpenes [50][51][52], flavonoids [30,53,54], Thai herbs [55], etc.) have antioxidant, antibacterial, restorative and antitumor properties, and, moreover, they are effective inhibitors of efflux pumps [3,5,6,9,[14][15][16][17]20,21,28,[56][57][58][59][60] that cause bacterial resistance to antibiotics and the resistance of cancer cells to cytostatics.…”

“…Apiol analogues (myristicin, allyltetramethoxybenzene and dillapiol) have also demonstrated weak antitumor activity, but they have served as a booster for antitumor drugs (paclitaxel, doxorubicin, cisplatin) [49] due to the inhibition of mitochondrial enzymes [81,82], efflux pumps [49] and the increased permeability of the membrane of cancer cells [49,83]. It was previously shown that dillapiol (25-50 µM) induced G0/G1 cell cycle arrest, the activation of a number of caspases and, accordingly, the apoptosis of cancer cells, while apiol and its analogues had virtually no effect on benign epithelial cells in vitro [46]. Myristicin showed a similar but weaker effect.…”

“…Myristicin showed a similar but weaker effect. Recently, triphenylphosphine (PPh 3 ) derivatives of allylbenzenes were suggested for research into improving their antiproliferative potency toward cancer cells taking into account their tendency to preferential mitochondrial accumulation [46]. The introduction of the PPh 3 moiety, possessing both hydrophobic and charged properties, enhances the conjugate's localization within the cell membrane and boosts inhibition against mitochondrial membrane enzymes.…”

Bifunctionalized Betulinic Acid Conjugates with C-3-Monodesmoside and C-28-Triphenylphosphonium Moieties with Increased Cancer Cell Targetability

“…Triphenylphosphonium (TPP) cation is a powerful modifier for improving pharmacological properties of different natural products, including triterpenoids. , In addition to better solubility, TPP derivatives typically possess increased bioavailability at cellular and whole body levels due to the delocalized cationic and lipophilic nature of TPP, which provides effective transportation through cellular membranes by natural electrochemical gradients. , Such ability also underlies preferable accumulation of TPP derivatives in mitochondria in proportion to the membrane potential, which was shown to be increased in different cancer cells …”