Synthesis, anticancer activity and effects on cell cycle profile and apoptosis of novel thieno[2,3-d]pyrimidine and thieno[3,2-e] triazolo[4,3-c]pyrimidine derivatives

Kandeel M.M.; Refaat H.M.; Kassab A.E.; Shahin I.G.; Abdelghany T.M.

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Synthesis, anticancer activity and effects on cell cycle profile and apoptosis of novel thieno[2,3-d]pyrimidine and thieno[3,2-e] triazolo[4,3-c]pyrimidine derivatives

Kandeel M.M.; Refaat H.M.; Kassab A.E.; Shahin I.G.; Abdelghany T.M.

Full Text link: https://t.ly/rx6A0

Date issued: 2015

Scientific Journal Rankings: Click Here

Doi: https://doi.org/10.1016/j.ejmech.2014.12.009 PubMed ID 25499930

Publisher: Elsevier Masson SAS

Series Info: European Journal of Medicinal Chemistry
90

Type: Article

Keywords: October University for Modern Sciences and Arts , University for Modern Sciences and Arts , MSA University , جامعة أكتوبر للعلوم الحديثة والآداب , Anticancer activity , Apoptosis , Cell cycle arrest profile , pyrimidines , Synthesis , Thieno[2,3-d]pyrimidines , Thieno[3,2-e]-1,2,4-triazolo[4,3-c] , 2 (1 naphthyl) 4 (4 phenylpiperazin 1 yl) 5,6,7,8,9,10 hexa hydrocycloocta [4,5]thieno[2,3 d]pyrimidine , 2 (1 naphthyl) 5,6,7,8,9,10 hexahydrocycloocta[4,5]thieno [2,3 d] pyrimidin 4(3h) one , 2 (3 pyridyl) 5,6,7,8,9,10 hexahydrocycloocta[4,5]thieno[2,3d]pyrimidin 4(3h) one , 3 (benzylthio) 5 (1 naphthyl) 8,9,10,11,12,13 hexahydrocycloocta[4,5]thieno[3,2 e] 1,2,4 triazolo[4,3 c]pyrimidine , 3 (benzylthio) 5 (3 pyridyl) 8,9,10,11,12,13 hexahydrocyclo octa[4,5]thieno[3,2 e] 1,2,4 triazolo[4,3 c]pyrimidine , 3 (ethylthio) 5 (3 pyridyl) 8,9,10,11,12,13 hexahydrocycloocta[4,5]thieno[3,2 e] 1,2,4 triazolo[4,3 c]pyrimidine , 3 (ethylthio) 5(1 naphthyl) 8,9,10,11,12,13 hexahydrocycloocta[4,5]thieno[3,2 e] 1,2,4 triazolo[4,3 c]pyrimidine , 4 (2 flouroanilino) 2 (1 naphthyl) 5,6,7,8,9,10 hexahydrocyclooct[4,5]thieno[2,3 d]pyrimidine , 4 (2 flouroanilino) 2 (3 pyridyl) 5,6,7,8,9,10 hexahydrocyclooct[4,5]thieno[2,3 d]pyrimidine , 4 (2 methoxyanilino) 2 (1 naphthyl) 5,6,7,8,9,10 hexahydro cyclooct[4,5]thieno[2,3 d]pyrimidine , 4 (2 methoxyanilino) 2 (3 pyridyl) 5,6,7,8,9,10 hexahydro cyclooct[4,5]thieno[2,3 d]pyrimidine , 4 (4 methoxyanilino) 2 (1 naphthyl) 5,6,7,8,9,10 hexahydro cyclooct[4,5]thieno[2,3 d]pyrimidine , 4 (4 methoxyanilino) 2 (3 pyridyl) 5,6,7,8,9,10 hexahydrocyclooct[4,5]thieno[2,3 d]pyrimidine , 4 (4 methylpiperazin 1 yl) 2 (1 naphthyl) 5,6,7,8,9,10 hexa hydrocycloocta[4,5]thieno[2,3 d]pyrimidine , 4 (4 methylpiperazin 1 yl) 2 (3 pyridyl) 5,6,7,8,9,10 hexahydrocycloocta[4,5]thieno[2,3 d]pyrimidine , 4 (4 phenylpiperazin 1 yl) 2 (3 pyridyl) 5,6,7,8,9,10 hexahydrocycloocta [4,5]thieno[2,3 d]pyrimidine , 4 (morpholin 4 yl) 2 (1 naphthyl) 5,6,7,8,9,10 hexahydrocycloocta[4,5]thieno[2,3 d]pyrimidine , 4 (morpholin 4 yl) 2 (3 pyridyl) 5,6,7,8,9,10 hexahydrocyclo octa[4,5]thieno[2,3 d]pyrimidine , 4 chloro 2 (1 naphthyl) 5,6,7,8,9,10 hexahydrocycloocta [4,5]thieno[2,3 d]pyrimidine , 4 chloro 2 (3 pyridyl) 5,6,7,8,9,10 hexahydrocycloocta[4,5] thieno[2,3 d]pyrimidine , 4 hydrazinyl 2 (1 naphthyl) 5,6,7,8,9,10 hexahydrocycloocta[4,5]thieno[2,3 d]pyrimidine , 4 hydrazinyl 2 (3 pyridyl) 5,6,7,8,9,10 hexahydrocycloocta [4,5]thieno[2,3 d]pyrimidine , 5 (1 naphthyl) 3 sulfanyl 8,9,10,11,12,13 hexahydrocycloocta[4,5]thieno[3,2 e] 1,2,4 triazolo[4,3 c]pyrimidine , 5 (3 pyridyl) 3 sulfanyl 8,9,10,11,12,13 hexahydrocycloocta [4,5]thieno[3,2 e] 1,2,4 triazolo[4,3 c]pyrimidine , antineoplastic agent , pyrimidine derivative , thieno[2,3 d]pyrimidine derivative , thieno[3,2 e] triazolo [4,3 c]pyrimidine derivative , unclassified drug , antineoplastic agent , pyrimidine derivative , thieno(2,3-d)pyrimidine , thieno(3,2-e)triazolo(4,3-c)pyrimidine , triazole derivative , antineoplastic activity , apoptosis , Article , breast cancer cell line , cancer cell line , cancer inhibition , cell cycle arrest , cell cycle progression , central nervous system tumor , colon cancer , drug structure , drug synthesis , G2 phase cell cycle checkpoint , human , human cell , leukemia cell line , M phase cell cycle checkpoint , melanoma , non small cell lung cancer , ovarian cancer cell line , prostate cancer cell line , proton nuclear magnetic resonance , renal cancer cell line , apoptosis , cell cycle , cell proliferation , chemical structure , chemistry , dose response , drug effects , drug screening , structure activity relation , synthesis , tumor cell line , Antineoplastic Agents , Apoptosis , Cell Cycle , Cell Line, Tumor , Cell Proliferation , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Pyrimidines , Structure-Activity Relationship , Triazoles

Abstract:

Motivated by the widely reported anticancer activity of thieno[2,3-d]pyrimidines a series of 24 new 2-substitutedhexahydrocycloocta[4,5] thieno[2,3-d]pyrimidines with different substituents at C-4 position and hexahydrocycloocta[4,5]thieno[3,2-e]-1,2,4-triazolo[4,3-c]pyrimidines were synthesized. The anticancer activity of 17 compounds were evaluated by National Cancer Institute (USA) using a two stage process utilizing 59 different human tumor cell lines representing leukemia, melanoma, cancers of lung, colon, central nervous system (CNS), ovary, kidney, prostate as well as breast. Compound 9c showed broad spectrum potent anticancer activity in nano molar to micro molar range against 56 human tumor cell lines with GI50 less than 10 ?M ranging from 0.495 to 5.57 mM, also it is worth mentioning that compound 9c had the marked highest selectivity against the two cell lines T-47D and MDA-MB-468 belonging to breast cancer with GI50 = 0.495 and 0.568 mM respectively, and its effect was further studied on cell cycle progression and induction of apoptosis in the MDA-MB-468 cell line. Results showed that compound 9c induced cell cycle arrest at G2/M phase and also, showed accumulation of cells in pre-G1 phase which may result from, degradation or fragmentation of the genetic materials indicating a possible role of apoptosis in compound 9c-induced cancer cell death and cytotoxicity and verifying this compound as promising selective anticancer lead. Compound 6c was selective against K-562, SR and MOLT-4 cell lines belonging to leukemia showing growth inhibition percentages 86.38, 65.76 and 60.40 at a single dose test, at the same time it showed lethal activity against HOP-92 representing non-small cell lung cancer. Interestingly, leukemia SR, CNS cancer SNB-75 and renal cancer UO-31 cell lines proved to be sensitive to compound 6d with growth inhibition percentages 52.86, 50.94 and 53.99 respectively. Additionally, compound 6d demonstrated lethal activity to HOP-92 belonging non-small cell lung cancer. � 2014 Elsevier Masson SAS.