Synthesis and anticancer activity of 1-(41-isopropylphenyl)-4-(42-chlorophenyl)5,6,7,8-tetrahydro-2,4а-diazacyclopenta[cd]azulene-2-carboxylic acid arylamides against PC-3 prostate cancer cells

Pharmacotherapy of prostate cancer is an important part in combating oncologic diseases. This is very relevant, because prostate cancer is a cause of 10 % of deaths from all cancerous diseases in males. The aim of the study – to synthesize novel derivatives of 1-(41-isopropylphenyl)-4-(42-chlorophenyl)5,6,7,8-tetrahydro-2,4а-diazacyclopenta[cd]azulene-2-carboxylic acid arylamides and to evaluate their antitumor activity against PC-3 prostate cancer cells. By reaction of equimolar amounts of 2-methoxy-3,4,5,6-tetrahydro-7H-azepine with a-amino-4-chloroacetophenone chlorohydrate, 3-(4-chlorophenyl)-6,7,8,9- tetrahydro-5Н-imidazo[1,2-a]azepine was synthesized. By alkylation of a-bromo-4-іsopropylacetophenone in ethylacetate and following treatment of the obtained intermediary quaternary salt with excess of 5 % NaOH solution,1-(41-isopropylphenyl)-4-(42chlorophenyl)-5,6,7,8-tetrahydro-2,4а-diazacyclopenta[cd] azulene was synthesized. By boiling it with equimolar amounts of correspondding arylisocyanates in dried benzol, an array of 1-(41-iso propylphenyl)-4(42-chlorophenyl)-5,6,7,8-tetrahydro-2,4а-diazacyclopenta[cd]azulene-2-carboxylic acid arylamides were synthesized. Structure and purity of all compounds obtained were confirmed by data of MR1Н spectroscopy. Lipophilicity (LogP) of compounds 6 and 8 a-i was calculated with the ACD LogP program. Antitumor activity of 1-(41-isopropylphenyl)-4-(42-chlorophenyl)-5,6,7,8-tetrahydro-2,4а-diazacyclopenta[cd]azulene-2-carboxylic acid (3-methylphenyl) and (3-methoxyphenyl)-amides was evaluated at in vitro test on prostate cancer PC-3 cell lines. It is indicated, that at concentration of 10–5 M these compounds exceed 5-fluorouracil as comparison drug in inhibiting PC-3 prostate cancer cells growth by 52.32 % and 3.93 % correspondingly. The data obtained substantiate feasibility of further studies of 1-(41-isopro pylphenyl)-4-(42-chlorophenyl)-5,6,7,8-tetrahydro-2,4а-diazacyclopenta[cd] azulene-2-carboxylic acid arylamides as new, potential antitumor medicines for prostate cancer treatment.

Synthesis and anticancer activity of 1-(41-isopropylphenyl)-4-(42-chlorophenyl)5,6,7,8-tetrahydro-2,4a-diazacyclopenta[ cd ]azulene-2-carboxylic acid arylamides against PC-3 prostate cancer cells

Pharmacotherapy of prostate cancer is an important part in combating oncologic diseases. This is very relevant, because prostate cancer is a cause of 10 % of deaths from all cancerous diseases in males. The aim of the study – to synthesize novel derivatives of 1-(41-isopropylphenyl)-4-(42-chlorophenyl)5,6,7,8-tetrahydro-2,4а-diazacyclopenta[cd]azulene-2-carboxylic acid arylamides and to evaluate their antitumor activity against PC-3 prostate cancer cells. By reaction of equimolar amounts of 2-methoxy-3,4,5,6-tetrahydro-7H-azepine with a-amino-4-chloroacetophenone chlorohydrate, 3-(4-chlorophenyl)-6,7,8,9- tetrahydro-5Н-imidazo[1,2-a]azepine was synthesized. By alkylation of a-bromo-4-іsopropylacetophenone in ethylacetate and following treatment of the obtained intermediary quaternary salt with excess of 5 % NaOH solution,1-(41-isopropylphenyl)-4-(42chlorophenyl)-5,6,7,8-tetrahydro-2,4а-diazacyclopenta[cd] azulene was synthesized. By boiling it with equimolar amounts of correspondding arylisocyanates in dried benzol, an array of 1-(41-iso propylphenyl)-4(42-chlorophenyl)-5,6,7,8-tetrahydro-2,4а-diazacyclopenta[cd]azulene-2-carboxylic acid arylamides were synthesized. Structure and purity of all compounds obtained were confirmed by data of MR1Н spectroscopy. Lipophilicity (LogP) of compounds 6 and 8 a-i was calculated with the ACD LogP program. Antitumor activity of 1-(41-isopropylphenyl)-4-(42-chlorophenyl)-5,6,7,8-tetrahydro-2,4а-diazacyclopenta[cd]azulene-2-carboxylic acid (3-methylphenyl) and (3-methoxyphenyl)-amides was evaluated at in vitro test on prostate cancer PC-3 cell lines. It is indicated, that at concentration of 10–5 M these compounds exceed 5-fluorouracil as comparison drug in inhibiting PC-3 prostate cancer cells growth by 52.32 % and 3.93 % correspondingly. The data obtained substantiate feasibility of further studies of 1-(41-isopro pylphenyl)-4-(42-chlorophenyl)-5,6,7,8-tetrahydro-2,4а-diazacyclopenta[cd] azulene-2-carboxylic acid arylamides as new, potential antitumor medicines for prostate cancer treatment.

Synthesis and antiviral properties derivatives of 1-(para-tolyl)-4-aryl-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulene-3-carbothioic acid arylamides

Nowadays, H1N1 – strain of so called «swine» or «mexican» subspecie A virus, which is still not studied, and which spreads through aerosol and contact is known to many world countries. Significant number of lethal cases during influenza pandemic season in Ukraine was observed. It should be noted, that patients went to the hospitals in very severe cases, which is why registered daily lethality is in 31,6% of cases. Everything listed above had made it necessary to conduct preventive measures on global and national levels. One of such measures is creation of new direct action medicinal agents. The goal of this work was the synthesis of compounds with potential antiviral properties in variety of 5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-3-carbotionic acid derivatives. We have chosen derivatives of 5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-3-carbotionic acid (6 a–e and 7 a–h), which were synthesized by boiling of 1-(para-tolyl)-4-aryl-5,6,7,8-tetrahydro-2,2a,4a-triazacyclopenta[cd]azulenes (5a or 5b) with corresponding arylisothiocyanates in dry benzene. Antiviral activity of phenylamid 1-(para-tolyl)-4-phenyl-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-3-carbotionic acid against Flu A H1N1 California/07/2009 was researched in Southern Research Institute – SRI, Birmingham, Alabama). Variety of new derivatives of 5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-3-carbotionic acid. Composition and structure of all synthesized compounds are proven by data of element analysis and 1Н NMR spectroscopy. In conducted researches of antiviral activity of phenylamide 1-(para-tolyl)-4-phenyl-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-3-carbotionic acid against Flu A H1N1 California/07/2009, it was found out, that synthesized compound shows pronounced antiviral activity, compared to reference medicinal agents Ribavirin and Amizon. Therefore, conducted researches confirm perspective of development of a new domestic medicinal agent with antiviral activity, based on derivatives of 5,6,7,8,-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-3-carbotionic acid.