Structure-Cytotoxicity Relationships of Analogues of N14-Desacetoxytubulysin H

  • J Med Chem. 2016 Dec 8;59(23):10781-10787. doi: 10.1021/acs.jmedchem.6b01023.
Dorin Toader  1  2 ,  Fengjiang Wang  1 ,  Lakshmaiah Gingipalli  1 ,  Melissa Vasbinder  1 ,  Mark Roth  1 ,  Shenlan Mao  3 ,  Michael Block  1 ,  Jay Harper  3 ,  Sambaiah Thota  1 ,  Mei Su  1 ,  Jianquo Ma  1 ,  Vahe Bedian  1 ,  Adeela Kamal  3
Affiliations
  • 1. Oncology iMED, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • 2. Antibody Discovery and Protein Engineering, MedImmune LLC , 1 MedImmune Way, Gaithersburg, Maryland 20878, United States.
  • 3. Oncology Research, MedImmune LLC , Gaithersburg, Maryland 20878, United States.
PMID: 27809515 DOI: 10.1021/acs.jmedchem.6b01023
Abstract

Herein we report structure-cytotoxicity relationships for analogues of N14-desacetoxytubulyisn H 1. A novel synthetic approach toward 1 enabled the discovery of compounds with a range of activity. Calculated basicity of the N-terminus of tubulysins was shown to be a good predictor of cytotoxicity. The impact of structural modifications at the C-terminus of 1 upon cytotoxicity is also described. These findings will facilitate the development of new tubulysin analogues for the treatment of Cancer.