Improved Total Synthesis of Tubulysins and Design, Synthesis, and Biological Evaluation of New Tubulysins with Highly Potent Cytotoxicities against Cancer Cells as Potential Payloads for Antibody-Drug Conjugates.
J Am Chem Soc
; 140(10): 3690-3711, 2018 03 14.
Article
em En
| MEDLINE
| ID: mdl-29381062
ABSTRACT
Improved, streamlined total syntheses of natural tubulysins such as V (Tb45) and U (Tb46) and pretubulysin D (PTb-D43), and their application to the synthesis of designed tubulysin analogues (Tb44, PTb-D42, PTb-D47-PTb-D49, and Tb50-Tb120), are described. Cytotoxicity evaluation of the synthesized compounds against certain cancer cell lines revealed a number of novel analogues with exceptional potencies [e.g., Tb111 IC50 = 40 pM against MES SA (uterine sarcoma) cell line; IC50 = 6 pM against HEK 293T (human embryonic kidney cancer) cell line; and IC50 = 1.54 nM against MES SA DX (MES SA with marked multidrug resistance) cell line]. These studies led to a set of valuable structure-activity relationships that provide guidance to further molecular design, synthesis, and biological evaluation studies. The extremely potent cytotoxic compounds discovered in these investigations are highly desirable as potential payloads for antibody-drug conjugates and other drug delivery systems for personalized targeted cancer chemotherapies.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oligopeptídeos
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Ácidos Pipecólicos
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Imunoconjugados
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Neoplasias
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
J Am Chem Soc
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos