Design and synthesis of a new class of cryptophycins based tubulin inhibitors

• Synthesized cryptophycins based macrocyclic depsipeptides without epoxide chain.
• Enantioselective cross-aldol reaction of acetaldehyde to synthesize Northern half.
• Lead analogues exhibited good anti-cancer activity and induced apoptosis.
• Caused block/delay in cell cycle and reduced the expression of α- and β-tubulins.
• Like cryptophycins bind to β-subunit of microtubule at α/β tubulin dimer interphase.

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.

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