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Design, Synthesis, and Cytotoxic Evaluation of Novel Tubulysin Analogues as ADC Payloads
journal contribution
posted on 2016-08-26, 00:00 authored by Carolyn A. Leverett, Sai Chetan K. Sukuru, Beth C. Vetelino, Sylvia Musto, Kevin Parris, Jayvardhan Pandit, Frank Loganzo, Alison
H. Varghese, Guoyun Bai, Bin Liu, Dingguo Liu, Sarah Hudson, Venkata Ramana Doppalapudi, Joseph Stock, Christopher J. O’Donnell, Chakrapani SubramanyamThe
tubulysin class of natural products has attracted much attention
from the medicinal chemistry community due to its potent cytotoxicity
against a wide range of human cancer cell lines, including significant
activity in multidrug-resistant carcinoma models. As a result of their
potency, the tubulysins have become an important tool for use in targeted
therapy, being widely pursued as payloads in the development of novel
small molecule drug conjugates (SMDCs) and antibody–drug conjugates
(ADCs). A structure-based and parallel medicinal chemistry approach
was applied to the synthesis of novel tubulysin analogues. These efforts
led to the discovery of a number of novel and potent cytotoxic tubulysin
analogues, providing a framework for our simultaneous report, which
highlights the discovery of tubulysin-based ADCs, including use of
site-specific conjugation to address in vivo stability of the C-11
acetate functionality.
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cancer cell linesC -11 acetate functionalitySMDCcytotoxic tubulysin analoguesCytotoxic EvaluationADC Payloadsnovel tubulysin analoguesmultidrug-resistant carcinoma modelschemistry communitytubulysin-based ADCsNovel Tubulysin Analoguessite-specific conjugationmolecule drug conjugateschemistry approachvivo stabilitytubulysin class
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