Abstract
A conformational restriction strategy was used to design and synthesize nine TZT-1027 analogues. 3-Aryl-azetidine moiety was used to replace phenylethyl group of TZT-1027 at the C-terminus. These analogues exhibited moderate to excellent antiproliferative activities, and the most potent compound 1a showed IC50 values of 2.2 nM against A549 and 2.1 nM against HCT116 cell lines, respectively. However, 1a could not achieve effective inhibition at all the dose levels in the A549 xenograft model (up to 5 mg/kg, injection, once a day), which is only 16%–35% inhibition at the end of the experiment.
Highlights
Dolastatin 10 and its natural analogues are highly-cytotoxic peptides isolated from the sea hareDolabella auricularia from the India Ocean [1]
The extraordinary cytotoxicity is caused by their ability to inhibit microtubule assembly and tubulin-dependent guanosine triphosphate (GTP) hydrolysis, which result in cell cycle arrest and apoptosis [3]
Some of them, such as TZT-1027, auristatin E, and auristatin PHE were advanced into clinical trials (Figure 1)
Summary
Dolastatin 10 and its natural analogues are highly-cytotoxic peptides isolated from the sea hare. Dolabella auricularia from the India Ocean [1]. These compounds have been demonstrated to be effective against a broad spectrum of cancer cells [2]. A large number of synthetic analogues of dolastatin. 10 have been reported [4,5,6] Some of them, such as TZT-1027, auristatin E, and auristatin PHE were advanced into clinical trials (Figure 1). MMAE, a monomethyl analog of Auristatin-E, was conjugated to monoclonal antibodies, leading to the discovery of the FDA approved ADC brentuximab vedotin (ADCETRIS) for the treatment of relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma [9]
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