RESUMO
Several novel spiro derivatives of parthenin (1) have been synthesized by the dipolar cycloaddition using various dipoles viz; benzonitrile oxides, nitrones and azides with exocyclic double bond of C ring (α-methylene-γ-butyrolactone). Majority of the compounds exhibited improved anti-cancer activity compared to the parthenin, when screened for their in vitro cytotoxicity against three human cancer cell lines viz., SW-620, DU-145 and PC-3. In vivo screening of select analog revealed improved anti-cancer activity with low mammalian toxicity as compared to parthenin. The results of the cytotoxicity pattern of these derivatives reveals the SAR of these sesquiterpinoid lactones and possible role of α,ß-unsaturated ketone of parthenin in inhibiting NF-kB. A mechanistic correlation of anti-cancer activity along with in vivo and western blotting experiments has been described.
Assuntos
Antineoplásicos/síntese química , Carcinoma de Ehrlich/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Sesquiterpenos/síntese química , Compostos de Espiro/síntese química , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , Animais , Antineoplásicos/farmacologia , Western Blotting , Carcinoma de Ehrlich/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Humanos , Masculino , Camundongos , NF-kappa B/metabolismo , Transplante de Neoplasias , Nitrilas/química , Óxidos/química , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Sesquiterpenos/farmacologia , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of novel 4beta-[(4-substituted)-1,2,3-triazol-1-yl]podophyllotoxin derivatives were synthesized by employing Cu(I)-catalyzed click chemistry and evaluated for their anticancer activity against a panel of seven human cancer cell lines (HT-29, HCT-15, 502713, HOP-62, A-549, MCF-7, and SF-295). The compounds 9b, 9c, 9e, 9f, and 9h showed significant cytotoxic activities especially against HT-29, HCT-15, 502713 cell lines.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Podofilotoxina/síntese química , Podofilotoxina/farmacologia , Triazóis/química , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Podofilotoxina/química , Relação Estrutura-AtividadeRESUMO
Four new ethylnitrosourea derivatives of substituted naphthalimides 3a-d have been synthesized from the respective N-(2-ethylamino) naphthalimides. Their chemical alkylating activity compared with the clinical drug CCNU and an experimental compound Mitonafide indicated that they possess lower alkylating activity than CCNU and comparable activity with the latter. Their anti-tumor efficacies were assessed in vivo in two murine ascites tumors namely Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times (MST) of drug treated (T) over untreated control (C) mice. CCNU and Mitonafide were used as positive controls for comparison. The representative compound 3a has displayed marginal anti-tumoral activity in these tumors. Three compounds were further screened in vitro in 4 different human tumor cell lines but no significant activity was observed in those lines. These compounds moderately inhibit the synthesis of DNA and RNA in S-180 tumor cells.