Synthetic Approaches Towards Tubulysins and Derivatives Thereof

Kazmaier, Uli; Ullrich, Angelika; Hoffmann, Judith

doi:10.2174/1874848101306010012

Cited by 15 publications

(5 citation statements)

References 70 publications

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“…The tubulysins are among the most potent cytotoxic compounds ever discovered from Nature. − Their mechanism of action involves depolymerization of microtubules with disintegration of the cytoskeleton as a consequence. − Isolated from the myxobacteria Archangium gephyra and Angiococcus disciformis , , these natural products elicited intense research efforts directed toward their total synthesis, analogue design and synthesis, and biological investigations as part of anticancer drug discovery and development programs. − Thus, total syntheses of the naturally occurring tubulysins A, B, C, D, − G, I, U ( Tb46 , Figure ), ,− and V ( Tb45 , Figure ) ,− and pretubulysin D ( PTb-D43 , Figure ), , as well as numerous analogues, have been accomplished. − From the latter, N 14 -desacetoxytubulysin H ( Tb1 , Figure ) is distinguished for its methyl, instead of the acyl methyl, substituent on N14 of tubulysins A–I ,− , and its high potency. , We have recently published a total synthesis of N 14 -desacetoxytubulysin H ( Tb1 , Figure ) and several of its analogues (e.g., Tb32 ,…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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: IC = 40 pM against MES SA (uterine sarcoma) cell line; IC = 6 pM against HEK 293T (human embryonic kidney cancer) cell line; and IC = 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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…Their impressive biological properties coupled with their natural scarcity stimulated intense research activities directed toward their chemical synthesis, structural modification, and biological evaluation. As a result of this surge, total syntheses of several naturally occurring tubulysins − (e.g., A, B, C, G and I, − U ,− and V, ,− and pretubulysin D; ,− Figure ) and analogues thereof have been reported. − Among the most interesting and potent of the latter is N 14 -desacetoxytubulysin H ( Tb1 ) (Figure ). ,, …”

Section: Introductionmentioning

confidence: 99%

Total Synthesis and Biological Evaluation of Natural and Designed Tubulysins

et al. 2016

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A streamlined total synthesis of N(14)-desacetoxytubulysin H (Tb1) based on a C-H activation strategy and a short total synthesis of pretubulysin D (PTb-D43) are described. Applications of the developed synthetic strategies and technologies to the synthesis of a series of tubulysin analogues (Tb2-Tb41 and PTb-D42) are also reported. Biological evaluation of the synthesized compounds against an array of cancer cells revealed a number of novel analogues (e.g., Tb14), some with exceptional potencies against certain cell lines [e.g., Tb32 with IC50 = 12 pM against MES SA (uterine sarcoma) cell line and 2 pM against HEK 293T (human embryonic kidney) cell line], and a set of valuable structure-activity relationships. The highly potent cytotoxic compounds discovered in this study are highly desirable as payloads for antibody-drug conjugates and other drug delivery systems for personalized targeted cancer chemotherapies.

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“…A crucial drawback of tubulysins is, as with other natural compounds, their sufficient supply. Fortunately, this obstacle has been overcome by the synthesis of simplified tubulysin derivatives [ 8 – 10 ], including pretubulysin (PT), a biosynthetic precursor of the tubulysins, which also acts as an MTA [ 11 ]. PT is chemically accessible and can be synthesized in the gram scale [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

The pretubulysin-induced exposure of collagen is caused by endothelial cell retraction that results in an increased adhesion and decreased transmigration of tumor cells

et al. 2017

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Microtubule-targeting agents (MTAs) are the most widely used chemotherapeutic drugs. Pretubulysin (PT), a biosynthetic precursor of the myxobacterial tubulysins, was recently identified as a novel MTA. Besides its strong anti-tumoral activities, PT attenuates tumor angiogenesis, exerts anti-vascular actions on tumor vessels and decreases cancer metastasis formation in vivo. The aim of the present study was to analyze the impact of PT on the interaction of endothelial and tumor cells in vitro to gain insights into the mechanism underlying its anti-metastatic effect. The influence of PT on tumor cell adhesion and transmigration onto/through the endothelium as well as its influence on cell adhesion molecules and the chemokine system CXCL12/CXCR4 was investigated. Treatment of human endothelial cells with PT increased the adhesion of breast cancer cells to the endothelial monolayer, whereas their transmigration through the endothelium was strongly reduced. Interestingly, the PT-induced upregulation of ICAM-1, VCAM-1 and CXCL12 were dispensable for the PT-evoked tumor cell adhesion. Tumor cells preferred to adhere to collagen exposed within PT-triggered endothelial gaps via β1-integrins on the tumor cell surface. Taken together, our study provides, at least in part, an explanation for the anti-metastatic potential of PT.

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Synthetic Approaches Towards Tubulysins and Derivatives Thereof

Cited by 15 publications

References 70 publications

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

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

Total Synthesis and Biological Evaluation of Natural and Designed Tubulysins

The pretubulysin-induced exposure of collagen is caused by endothelial cell retraction that results in an increased adhesion and decreased transmigration of tumor cells

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