title: Design and synthesis of a new class of cryptophycins based tubulin inhibitors.
abstract: Tubulin binding compounds represent one of the most attractive targets for anticancer drug development. They broadly fall into two categories viz., tubulin polymerization inhibitors, which block microtubule growth and destabilize microtubules like vinca alkaloids and cryptophycins, and the others, which polymerize microtubules into hyperstable forms represented by family of taxanes. In this context, we aimed at design and synthesis of cryptophycins based macrocyclic depsipeptides, which are synthetically more accessible, however have the basic information to target tubulins and establish structure activity relationship (SAR). Thus, a new class of cryptophycins based marocyclic depsipeptides with a truncated epoxide chain were synthesized as potential tubulin inhibitors. The resultant lead analogues 15a and 16a exhibited good anti-cancer activity, induced apoptosis, caused block/delay in cell cycle as well as significantly reduced the expression of α- and β-tubulins. Molecular modelling studies show that 15a and 16a bind in the same domain as that of cryptophycins.
authors: Academy of Scientific and Innovative Research (AcSIR), India; Natural Product Microbes, CSIR-Indian Institute of Integrative Medicine Jammu, J & K, 180001, India.
authors: Arvind
authors: A
authors: Kumar
authors: Academy of Scientific and Innovative Research (AcSIR), India; Natural Product Microbes, CSIR-Indian Institute of Integrative Medicine Jammu, J & K, 180001, India.
authors: Manjeet
authors: M
authors: Kumar
authors: Natural Product Microbes, CSIR-Indian Institute of Integrative Medicine Jammu, J & K, 180001, India.
authors: Simmi
authors: S
authors: Sharma
authors: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine Jammu, J & K, 180001, India.
authors: Santosh Kumar
authors: SK
authors: Guru
authors: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine Jammu, J & K, 180001, India.
authors: Shashi
authors: S
authors: Bhushan
authors: Academy of Scientific and Innovative Research (AcSIR), India; Natural Product Microbes, CSIR-Indian Institute of Integrative Medicine Jammu, J & K, 180001, India. Electronic address: bashah@iiim.ac.in.
authors: Bhahwal Ali
authors: BA
authors: Shah
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003500:Cyclization; D003598:Cytoskeletal Proteins / Q000378:metabolism; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D003598:Cytoskeletal Proteins; D047630:Depsipeptides; D050257:Tubulin Modulators
keywords: Anti-cancer; Asymmetric aldol; Cryptophycins; Macrocyclic depsipeptides; Tubulin inhibitors