title: Synthesis and antiproliferative activity of monocationic arylthiophene derivatives.
abstract: Eleven compounds of substituted 4-(5-arylthiophen-2-yl)benzamidines 4a-k were synthesized from their corresponding mononitriles via treatment with lithium trimethylsilylamide and subsequent de-protection with ethanol/hydrogen chloride. In vitro antiproliferative activities of the new monocationic arylthiophenes were evaluated against 60 human cell lines at NCI, USA. This class of compounds displayed promising submicromolar antiproliferative activities with the most potent compound being 4i (GI50and TGI of 0.20 and 0.37 μM, respectively). On the other hand, most of the tested compounds exhibited LC50at concentrations much higher than those they had GI50at; ∼10× (for 4b) up to 228× (for 4e) which indicates lower lethality and efficient growth inhibition. Cancer cell lines, HCC-2998 colon, SNB-75 CNS, MDA-MB-435 melanoma, and MCF-7 breast cancer were the most responsive, with GI50sof 0.156, 0.165, 0.163, and 0.168 μM, respectively. The p-chlorophenyl derivatives 4e and 4i discerned themselves with GI50values at 0.36 and 0.20 μM, respectively, and LC50values at ∼83 and 36 μM, respectively, but safe to RBCs at 1000 μM. The cytotoxic activity data of these compounds in two normal cell lines; WI38 and WISH proved that they are very safe on normal cells. The plausible mechanism of action of the tested monocations was examined by evaluating their antioxidant power, nuclease-like DNA degradation aptitude and tyrosine kinase (TK) inhibition activities. The tested monocations showed potent activity in all assays. Compounds 4e and 4i caused 88 and 98%, respectively, inhibition in TK activity at 1 μM and the IC50for 4i was 13 nM. The tested monocations have selective anticancer activity without insulting normal cells most probably due to inhibition of the key enzyme TK at nanomolar concentrations.
authors.affiliation: King Faisal University, College of Science, Department of Chemistry, Hofuf 31982, Saudi Arabia; Department of Chemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt. Electronic address: ismail_158@yahoo.com.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Ismail
authors.affiliation: King Faisal University, College of Science, Department of Chemistry, Hofuf 31982, Saudi Arabia; Department of Chemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt.
authors.forename: Magdy M
authors.initials: MM
authors.lastname: Youssef
authors.affiliation: Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Cairo 12588, Egypt.
authors.forename: Reem K
authors.initials: RK
authors.lastname: Arafa
authors.affiliation: King Faisal University, College of Science, Department of Chemistry, Hofuf 31982, Saudi Arabia.
authors.forename: Shar S
authors.initials: SS
authors.lastname: Al-Shihry
authors.affiliation: University of Ain Shams, Faculty of Science, Department of Zoology, Abbassia, Cairo 11566, Egypt. Electronic address: waelelhalawany@hotmail.com.
authors.forename: Wael M
authors.initials: WM
authors.lastname: El-Sayed
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000975:Antioxidants; D001550:Benzamidines / Q000737:chemistry; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012680:Sensitivity and Specificity; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D001550:Benzamidines; D013876:Thiophenes; D011505:Protein-Tyrosine Kinases
keywords: Antiproliferative activity; DNA affinity; Monocationic arylthiophenes; Suzuki coupling; tyrosine kinase inhibition