Hybrid Molecules Based on C₆₀ Fullerene and 5Z,9Z‐Dienoic Acids: Synthesis and Cytotoxic Activity

Abstract

The present research addresses synthesis of methanofullerenes containing 5Z,9Z-dienoic acid molecules applying the Bingel and Bingel-Hirsch reactions. The cytotoxic activity of the synthesized methanofullerenes against Jurkat, K562, U937, HL60 tumour cells was under study. Hybrid methanofullerenes containing dienoic acids were found to exhibit high in vitro cytotoxicity against these tumour cell lines, produce phasespecific cytotoxic effect during the S and G2 phases of the cell cycle, and are also effective inducers of apoptosis.Building effective systems for targeted drug delivery in the development of anticancer drugs is one of the major challenges of modern pharmacology. This is due to the fact that most antitumor drugs are highly toxic and lack specificity, meaning that these treatments affect both cancer cells and their normal counterparts.No coincidence is the fact that the range of nanoscale delivery vectors of anticancer drugs has expanded significantly since the discovery of fullerenes in 1985. The size, shape and high lipophilicity of C 60 fullerene enable it to penetrate rather easily through cell membranes and are an ideal combination of properties for use as a vector for targeted drug delivery.To date, the transport properties of C 60 fullerene have been successfully demonstrated on a wide range of different pharmaceutical products and anticancer drugs. A perfect example of the use of C 60 fullerene as a means of anticancer drug delivery with the aim of increasing their selectivity is the production of complexes and hybrids with doxorubicin. [1][2][3][4][5][6][7][8] Individual doxorubicin is characterized by low selectivity and cardiotoxicity, its fullerene complex increases both the rate of penetration into cancer cells by 20-30% and the effectiveness increases by 1.5-2 times. [1] The conjugate of doxorubicin with C 60 reduces the tumor volume by 40-60% in vivo compared to an individual doxorubicin, thus increasing life expectancy of mice by 2.5 times. [1,2] Furthermore, enhanced efficiency of the conjugate does not increase the side effects of the initial preparation. [4,5] Chemical binding of C 60 fullerene and its derivatives with doxorubicin does not produce obvious therapeutic effect of this kind, [6,7] but there is still a significant decline in the toxicity of the initial anticancer drug. [7] The main difference between the hybrid and the original doxorubicin molecules is that the hybrid, after penetrating the cell, primarily accumulates in the cytoplasm, and not in the nucleus. [8] Along with doxorubicin, C 60 fullerene complexes and hybrids were also prepared with paclitaxel, [9,10] docetaxel, [11 ] and cisplatin. [12,13] Increased effectiveness of the corresponding drugs was reached with achieved both in vivo and in vitro experiments. Meanwhile, when comparing the therapeutic effect, a considerable decline in the toxicity of these drugs was registered as well.Recently, our research group developed an efficient onepot method for the synthesis of 5Z,9Z-dienoic acids with a yield of ∼ 70% an...

Therapeutic potential of 1,2,3‐triazole hybrids for leukemia treatment

“…[94] The 1,2,3-triazole-fullerene hybrids 46 (IC 50 : 28 and 44 nM, MTT assay) exhibited profound activity against K562 and HL-60 leukemia cell lines, and the activity was far superior to that of camptothecin (IC 50 : 934 and 781 nM). [95] The SAR illustrated that the 1,2,3-triazole moiety was critical for the high activity, and the removal of this fragment resulted in a great loss of activity. Mechanistically, these hybrids arrested G2 and S phases and induced apoptosis.…”

“…Mechanistically, these hybrids arrested G2 and S phases and induced apoptosis. [ 96 ] Overall, these hybrids were worthy of further evaluation.…”