title: Exploring Derivatives of Quinazoline Alkaloid l-Vasicine as Cap Groups in the Design and Biological Mechanistic Evaluation of Novel Antitumor Histone Deacetylase Inhibitors.
abstract: l-Vasicine is a quinazoline alkaloid with an electron dense ring and additional functionalities in its structure. Employing target oriented synthesis (TOS) based on in silico studies, molecules with significant docking scores containing different derivatives of l-vasicine as caps were synthesized. Interestingly, one molecule, i.e., 4a, which contained 3-hyroxypyrrolidine as a cap group and a six carbon long aliphatic chain as a linker was found to inhibit HDACs. 4a showed more specificity toward class I HDAC isoforms. Also 4a was found to be less cytotoxic toward normal cell lines as compared to cancer cell lines. 4a inhibited cancer cell growth and induced cell death by various mechanisms. However, 4a was found to induce cell death independent of ROS generation, and unlike many natural product based HDAC inhibitors, 4a was found to be nontoxic under in vivo conditions. Importantly, we for the first time report the possibility of using a 3-hydroxypyrrolidine cap for the synthesis of HDAC inhibitors with good potency.
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu-180001, India.
authors.forename: Mudassier
authors.initials: M
authors.lastname: Ahmad
authors.forename: Mushtaq A
authors.initials: MA
authors.lastname: Aga
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu-180001, India.|Department of Biotechnology, Panjab University , Chandigarh-160014, India.
authors.forename: Javeed Ahmad
authors.initials: JA
authors.lastname: Bhat
authors.forename: Brijesh
authors.initials: B
authors.lastname: Kumar
authors.forename: Abdul
authors.initials: A
authors.lastname: Rouf
authors.affiliation: Department of Biotechnology, Panjab University , Chandigarh-160014, India.
authors.forename: Neena
authors.initials: N
authors.lastname: Capalash
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu-180001, India.|CSIR-Academy of Scientific & Innovative Research , New Delhi, India.
authors.forename: Mubashir Javeed
authors.initials: MJ
authors.lastname: Mintoo
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Discovery Informatics Division, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu-180001, India.
authors.forename: Priya
authors.initials: P
authors.lastname: Mahajan
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu-180001, India.|CSIR-Academy of Scientific & Innovative Research , New Delhi, India.
authors.forename: Dilip Manikrao
authors.initials: DM
authors.lastname: Mondhe
authors.affiliation: Discovery Informatics Division, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu-180001, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Nargotra
authors.affiliation: CSIR-Academy of Scientific & Innovative Research , New Delhi, India.
authors.forename: Parduman Raj
authors.initials: PR
authors.lastname: Sharma
authors.affiliation: Department of Biochemistry, University of Kashmir , Srinagar, Jammu and Kashmir-190006, India.
authors.forename: Mohmmad Afzal
authors.initials: MA
authors.lastname: Zargar
authors.forename: Ram A
authors.identifier: 0000-0002-0752-6238
authors.initials: RA
authors.lastname: Vishwakarma
authors.affiliation: CSIR-Academy of Scientific & Innovative Research , New Delhi, India.
authors.forename: Bhahwal Ali
authors.initials: BA
authors.lastname: Shah
authors.forename: Subhash Chandra
authors.initials: SC
authors.lastname: Taneja
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu-180001, India.|CSIR-Academy of Scientific & Innovative Research , New Delhi, India.
authors.forename: Abid
authors.identifier: 0000-0002-3969-1449
authors.initials: A
authors.lastname: Hamid
mesh_terms: D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D011799:Quinazolines; C019592:vasicine