10.1021/acsmedchemlett.6b00274.s001 Carolyn A. Leverett Carolyn A. Leverett Sai Chetan K. Sukuru Sai Chetan K. Sukuru Beth C. Vetelino Beth C. Vetelino Sylvia Musto Sylvia Musto Kevin Parris Kevin Parris Jayvardhan Pandit Jayvardhan Pandit Frank Loganzo Frank Loganzo Alison H. Varghese Alison H. Varghese Guoyun Bai Guoyun Bai Bin Liu Bin Liu Dingguo Liu Dingguo Liu Sarah Hudson Sarah Hudson Venkata Ramana Doppalapudi Venkata Ramana Doppalapudi Joseph Stock Joseph Stock Christopher J. O’Donnell Christopher J. O’Donnell Chakrapani Subramanyam Chakrapani Subramanyam Design, Synthesis, and Cytotoxic Evaluation of Novel Tubulysin Analogues as ADC Payloads American Chemical Society 2016 cancer cell lines C -11 acetate functionality SMDC cytotoxic tubulysin analogues Cytotoxic Evaluation ADC Payloads novel tubulysin analogues multidrug-resistant carcinoma models chemistry community tubulysin-based ADCs Novel Tubulysin Analogues site-specific conjugation molecule drug conjugates chemistry approach vivo stability tubulysin class 2016-08-26 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Design_Synthesis_and_Cytotoxic_Evaluation_of_Novel_Tubulysin_Analogues_as_ADC_Payloads/3810699 The 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.