A novel nano-formulation of the anticancer drug cisplatin (Cis) with C 60 fullerene (C 60 +Cis complex) was developed, demonstrating enhanced cytotoxic activity towards tumor cell lines in vitro n comparison to Cis alone. The enhanced proapoptotic activity of the novel complexes was found to be tightly connected with their unique capability to circumvent cancer drug resistance in vitro, as revealed by investigation of human leukemia cells HL-60 together with their sublines resistant towards doxorubicin (HL-60/adr, multidrug resistance protein-1=MRP-1=ABCC1 overexpressing) and vincristine (HL-60/vinc, P-glycoprotein=P-gp=ABCB1 overexpressing). The enhanced anticancer activity of the developed С 60 +Cis complexes was also confirmed in vivo on male C57BL/6J mice bearing Lewis lung carcinoma, effectively inhibiting tumor growth and formation of metastases in comparison to free single Cis. For better understanding of molecular mechanisms underlying the potential ability of the С 60 +Cis complexes to circumvent cancer drug resistance, a molecular docking study was conducted. This analysis demonstrated the potential capability of C 60 fullerene to form van der Waals interactions with potential binding sites of P-gp, MRP-1and MRP-2 (ABCC2) molecules, with maximum affinity to MRP-2. The observed phenomenon might indicate the mechanism how the C 60 +Cis complex bypasses drug resistance of cancer cells by direct binding to ABC transporter proteins. Additionally, the results of Ames mutagenicity test demonstrated that immobilization of Cis on С 60 fullerene significantly diminishes mutagenic activity of Cis and may reduce the probability of secondary neoplasms induction. Concluding, the synthesized C 60 +Cis complex effectively induces cancer cell death in vitro and inhibits tumor growth in vivo, circumventing cancer cell resistance to chemotherapy due to the specific affinity of C 60 fullerene towards ABC-transporter proteins. The obtained results indicate the C 60 +Cis complex as a promising novel chemotherapeutic agentespecially for treatment of drug-resistant tumors.

An approach to the parallel synthesis of hydantoin libraries by reaction of in situ generated 2,2,2-trifluoroethylcarbamates and α-amino esters was developed. To demonstrate utility of the method, a library of 1158 hydantoins designed according to the lead-likeness criteria (MW 200-350, cLogP 1-3) was prepared. The success rate of the method was analyzed as a function of physicochemical parameters of the products, and it was found that the method can be considered as a tool for lead-oriented synthesis. A hydantoin-bearing submicromolar primary hit acting as an Aurora kinase A inhibitor was discovered with a combination of rational design, parallel synthesis using the procedures developed, in silico and in vitro screenings.

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