Metal-Based Anticancer Complexes and p53: How Much Do We Know?

P53 plays a key role in protecting the human genome from DNA-related mutations; however, it is one of the most frequently mutated genes in cancer. The P53 family members p63 and p73 were also shown to play important roles in cancer development and progression. Currently, there are various organic molecules from different structural classes of compounds that could reactivate the function of wild-type p53, degrade or inhibit mutant p53, etc. It was shown that: (1) the function of the wild-type p53 protein was dependent on the presence of Zn atoms, and (2) Zn supplementation restored the altered conformation of the mutant p53 protein. This prompted us to question whether the dependence of p53 on Zn and other metals might be used as a cancer vulnerability. This review article focuses on the role of different metals in the structure and function of p53, as well as discusses the effects of metal complexes based on Zn, Cu, Fe, Ru, Au, Ag, Pd, Pt, Ir, V, Mo, Bi and Sn on the p53 protein and p53-associated signaling.

Synthesis and Antiproliferative Activity of Triphenylphosphonium Derivatives of Natural Allylpolyalkoxybenzenes.

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.

Sea Urchin Embryo Model As a Reliable in Vivo Phenotypic Screen to Characterize Selective Antimitotic Molecules. Comparative evaluation of Combretapyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles as Tubulin-Binding Agents.

A series of both novel and reported combretastatin analogues, including diarylpyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles, were synthesized via improved protocols to evaluate their antimitotic antitubulin activity using in vivo sea urchin embryo assay and a panel of human cancer cells. A systematic comparative structure-activity relationship studies of these compounds were conducted. Pyrazoles 1i and 1p, isoxazole 3a, and triazole 7b were found to be the most potent antimitotics across all tested compounds causing cleavage alteration of the sea urchin embryo at 1, 0.25, 1, and 0.5 nM, respectively. These agents exhibited comparable cytotoxicity against human cancer cells. Structure-activity relationship studies revealed that compounds substituted with 3,4,5-trimethoxyphenyl ring A and 4-methoxyphenyl ring B displayed the highest activity. 3-Hydroxy group in the ring B was essential for the antiproliferative activity in the diarylisoxazole series, whereas it was not required for potency of diarylpyrazoles. Isoxazoles 3 with 3,4,5-trimethoxy-substituted ring A and 3-hydroxy-4-methoxy-substituted ring B were more active than the respective pyrazoles 1. Of the azoles substituted with the same set of other aryl pharmacophores, diarylpyrazoles 1, 4,5-diarylisoxazoles 3, and 4,5-diaryl-1,2,3-triazoles 7 displayed similar strongest antimitotic antitubulin effect followed by 3,4-diarylisoxazoles 5, 1,5-diaryl-1,2,3-triazoles 8, and pyrroles 10 that showed the lowest activity. Introduction of the amino group into the heterocyclic core decreased the antimitotic antitubulin effect of pyrazoles, triazoles, and to a lesser degree of 4,5-diarylisoxazoles, whereas potency of the respective 3,4-diarylisoxazoles was increased.