Irina G. Tkachenko

Background/Objectives: Here, we report on the synthesis and biological evaluation of a novel peptide–drug conjugate, P6-SN38, which consists of the EGFR-specific short cyclic peptide, P6, and the Topo I inhibitor SN38, which is a bioactive metabolite of the anticancer drug irinotecan. Methods: SN38 is attached to the peptide at position 20 of the E ring’s tertiary hydroxyl group via a mono-succinate linker. Results: The developed peptide–drug conjugate (PDC) exhibited sub-micromolar anticancer activity on EGFR-positive (EGFR+) cell lines but no effect on EGFR-negative (EGFR−) cells. In vivo studies have shown that this PDC specifically accumulates in EGFR+ non-small cell lung cancer (NSCLC) xenografts and presents superior anticancer activity compared to the EGFR-specific antibody cetuximab (Erbitux^TM) and free SN38. The 10 mg/kg dose of P6-SN38 in a side-by-side EGFR+/EGFR− xenograft shows eradication of the EGFR+ tumor with good tolerance, but no inhibition of tumor growth of the EGFR− counterpart. Conclusions: The PDC examined in this study was proven to be highly efficient for NSCLC, broadening its utilization for targeted cancer therapy in EGFR overexpressed cancers.

The three-component reaction of 5-aminotetrazole with aliphatic aldehydes (formaldehyde, acetaldehyde) and acetoacetic ester derivatives in water under microwave irradiation leads to the selective formation of 4,7-dihydrotetrazolo[1,5-a]pyrimidine derivatives. Under similar conditions using 4,4,4-trifluoroacetoacetic ester 5-hydroxy-4,5,6,7-tetrahydrotetrazolo[1,5-a]pyrimidines are obtained. The analogous reaction with acetylacetone requires scandium(III) triflate as catalyst. The antioxidant activity of selected compounds was assayed with 1,1-diphenyl-2-picrylhydrazyl.

Multicomponent reaction of 3-amino-5-methylpyrazole, aliphatic aldehyde (paraformaldehyde or acetaldehyde) and acetylacetone in water by conventional heating, microwave or ultrasound activation undergoes on molar amounts of reagents 2:1:2, respectively, leads bis(2,5,7-trimethylpyrazolo[1,5-a]pyrimidin-6-yl)-substituted methane or to corresponding 1,1-bis-substituted ethane.