Design, synthesis and pharmacological evaluation of novel pyrrolizine derivatives as potential anticancer agents.
A new series of novel pyrrolizine derivatives has been synthesized and biologically evaluated as potential anticancer agents. The starting compounds, 6-amino-7-cyano-N-(3,5-disubstitutedphenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamides 11a-b, were reacted with different acid chlorides, aldehydes and isocyanates to give the target compounds 12-14. Structural characterizations of the new compounds were performed using spectral and elemental analysis. All compounds were tested for their anticancer activity against human breast cancer and prostate cancer cell lines, MCF-7 and PC-3 respectively. With exception of compounds 11a and 13a, results revealed that all the tested compounds showed half maximal inhibitory concentration (IC50) values less than 40μM. Compound 12b and the three urea derivatives 14b-d showed the most potent anticancer activity with IC50 values less than 2.73μM. The anticancer activity of these compounds was mediated, at least in part, via the induction of apoptosis as indicated by its ability to activate caspase-3/7. In light of the high potency of our novel compounds in targeting both breast and prostate cancers, these compounds warrant continued preclinical development as potential anticancer agents.
Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, Umm Al-Qura University, Mekkah 21955, Saudi Arabia.
Ahmed M
AM
Gouda
Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif 21974, Saudi Arabia.
Ahmed H
AH
Abdelazeem
Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
El-Shaimaa A
el-SA
Arafa
Department of Pharmaceutical Organic Chemistry, Beni-Suef University, Beni-Suef 62514, Egypt. Electronic address: khaled.ahmed@pharm.bsu.edu.eg.
Khaled R A
KR
Abdellatif
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D061986:MCF-7 Cells; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000970:Antineoplastic Agents; D011758:Pyrroles; C013231:pyrroline; D053148:Caspase 3; D053179:Caspase 7
Apoptosis; Breast cancer; Caspase activation; Prostate cancer; Pyrrolizine