Search

As a result of the implementation of two approaches, the Pudovik reaction (the reaction of macrocyclic azomethines with secondary phosphine oxides) and the Kabachnik–Fields reaction (three-component one-pot process involving dialdehydes, diamines, and secondary phosphine oxides), novel N,O-containing macrocyclic ligands with phosphine oxide groups were first obtained. The synthesized macrocycles are a kind of α-aminophosphoryl compounds that can be used in the synthesis of supramolecular systems.

New C(6)-derivatives of natural phaeosphaeride A (PPA) modified with pharmacophoric nitrogen heterocyclic groups have been synthesized. The reaction of 1,2,4-triazole with PPA mesylate produced both the product of the expected substitution of the methanesulfonate group and the PPA derivative with two 1,2,4-triazole groups: at the C(6) atom and the exocyclic C=C bond. The synthesized compounds, with the exception of those containing two 1,2,4-triazole groups, are superior in cytotoxic activity to the original phaeosphaeride and the positive control, etoposide.

New derivatives of phaeosphaeride A (PPA) were synthesized and characterized. Anti-tumor studies were carried out on the U937, HCT-116, PC3, MCF-7, A549, К562, NCI-H929, Jurkat, THP-1, RPMI8228 tumor cell lines, and on the HEF cell line. All the compounds synthesized were found to have better efficacy than PPA towards the tumor cell lines mentioned. Compound 6 (IC50 = 0.59 ± 0.27 µM) was observed to be 11 times more active than PPA (IC50 = 6.5 ± 0.30 µM) towards the NCI-H929 cell line, with a therapeutic index of 18. Compound 6 was determined to be over half and 16 times more active than etoposide towards the NCI-H929 (IC50 = 0.9 ± 0.05 µM) and A549 (IC50 = 100 ± 7.0 µM) cell lines, respectively.

6-O-Acylated phaeosphaeride A and phaeosphaeride B in reaction with secondary cyclic amines undergo stereospecific replacement of acyloxy group by pharmacophoric amino moiety. In case of chloroacetoxy derivative, chlorine displacement by such amines proceeds in the presence of triethylamine.

New derivatives of phaeosphaeride A (PPA) were synthesized and characterized. Anti-tumor activity studies were carried out on the HCT-116, PC3, MCF-7, A549, К562, NCI-Н929, Jurkat, THP-1, RPMI8228 tumor cell lines, and on the HEF cell line. All of the compounds synthesized were found to have better efficacy than PPA towards the tumor cell lines mentioned. Compound 6 was potent against six cancer cell lines, HCT-116, PC-3, K562, NCI-H929, Jurkat, and RPMI8226, showing a 47, 13.5, 16, 4, 1.5, and 7-fold increase in anticancer activity comparative to those of etoposide, respectively. Compound 1 possessed selectivity toward the NCI-H929 cell line (IC50 = 1.35 &plusmn, 0.69 &mu, M), while product 7 was selective against three cancer cell lines, HCT-116, MCF-7, and NCI-H929, each having IC50 values of 1.65 &mu, M, 1.80 &mu, M and 2.00 &mu, M, respectively.

The herein synthesized 7-(4-methylphenyl)thiomethyl and 7-morpholylmethyl derivatives of natural phaeosphaeride A have lower cytotoxic activity towards the human lung adenocarcinoma A549 cell line compared to phaeosphaeride A. The presence of exocyclic C=C bond and N–OMe group in such compounds is suggested to be a factor in their antitumor activity.