title: Chalcone based azacarboline analogues as novel antitubulin agents: design, synthesis, biological evaluation and molecular modelling studies.
abstract: The present study involves the design of a series of 3-aryl-9-acetyl-pyridazino[3,4-b]indoles as constrained chalcone analogues. A retrosynthetic route was proposed for the synthesis of target compounds. All the synthesized compounds were evaluated for in-vitro cytotoxicity against THP-1, COLO-205, HCT-116 and A-549 human cancer cell lines. The results indicated that 2a, 3a, 5a and 6a possessed significant cytotoxic potential with an IC50 value ranging from 1.13 to 5.76 μM. Structure activity relationship revealed that the nature of both Ring A and Ring B influences the activity. Substitution of methoxy groups on the phenyl ring (Ring A) and unsubstituted phenyl ring (Ring B) were found to be the preferred structural features. The most potent compound 2a was further tested for tubulin inhibition. Compound 2a was found to significantly inhibit the tubulin polymerization (IC50 value - 2.41 μM against THP-1). Compound 2a also caused disruption of microtubule assembly as evidenced by Immunoflourescence technique. The significant cytotoxicity and tubulin inhibition by 2a was rationalized by molecular modelling studies. The most potent structure was docked at colchicine binding site (PDB ID-1SA0) and was found to be stabilized in the cavity via various hydrophobic and hydrogen bonding interactions.
authors.affiliation: Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
authors.forename: Sahil
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
authors.forename: Charanjit
authors.initials: C
authors.lastname: Kaur
authors.affiliation: Faculty of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, India.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Budhiraja
authors.affiliation: Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India. Electronic address: kunal_8855@gmail.com.
authors.forename: Kunal
authors.initials: K
authors.lastname: Nepali
authors.affiliation: Molecular Modeling and Pharmacoinformatics Lab, Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab 143005, India; Lloyd Institute of Management and Technology, Greater Noida, UP, India.
authors.forename: Manish K
authors.initials: MK
authors.lastname: Gupta
authors.affiliation: Indian Institute of Integrative Medicine, Jammu, India.
authors.forename: A K
authors.initials: AK
authors.lastname: Saxena
authors.affiliation: Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
authors.forename: P M S
authors.initials: PM
authors.lastname: Bedi
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002599:Chalcone / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002243:Carbolines; D050257:Tubulin Modulators; D002599:Chalcone
keywords: Carboline; Cell line; Chalcone; Constrained; Cytotoxic; Molecular modelling studies; Tubulin