Structure-Cytotoxicity Relationships of Analogues of N14-Desacetoxytubulysin H.
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.
Oncology iMED, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.|Antibody Discovery and Protein Engineering, MedImmune LLC , 1 MedImmune Way, Gaithersburg, Maryland 20878, United States.
Dorin
D
Toader
Oncology iMED, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Fengjiang
F
Wang
Oncology iMED, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Lakshmaiah
L
Gingipalli
Oncology iMED, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Melissa
M
Vasbinder
Oncology iMED, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Mark
M
Roth
Oncology Research, MedImmune LLC , Gaithersburg, Maryland 20878, United States.
Shenlan
S
Mao
Oncology iMED, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Michael
M
Block
Oncology Research, MedImmune LLC , Gaithersburg, Maryland 20878, United States.
Jay
J
Harper
Oncology iMED, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Sambaiah
S
Thota
Oncology iMED, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Mei
M
Su
Oncology iMED, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Jianquo
J
Ma
Oncology iMED, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Vahe
V
Bedian
Oncology Research, MedImmune LLC , Gaithersburg, Maryland 20878, United States.
Adeela
A
Kamal
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; C520247:N14-desacetoxytubulysin H; D009842:Oligopeptides