O

7.04.2.1.2 Peptides and depsipeptides

7.04.2.1.2.1 Dolastatins

Dolastatin 10 25 (Figure 8), a linear pentapeptide, was originally isolated from the extracts of the sea hare Dolabella auriculari. It has since been isolated directly from a dietary cyanobacterium, Symploca species.71-73 With ED50 values as low as 4.6 x 10_5ngmL_ 1 dolastatin 10 was the most potent antiproliferative compound known at the time of its isolation. The antimitotic activity of this compound results from both its inhibition of microtubule formation and its inhibition of tubulin-dependent GTP hydrolysis.74 It was these findings, as well as the noncompetitive inhibition of vincristine binding to tubulin, that led to a distinct tubulin binding site (peptide site) being proposed. This site is proximal to both the vinca and exchangeable GTP sites and exists for dolastatin 10 and related peptide agents.75'76 Promising preclinical data led to clinical evaluation of dolastatin 10.77,78 Although dolastatin 10 was ultimately not successful in human clinical trials, it did progress to phase II and served as the parent compound for a number of structurally related clinical candidates.79,80 These include auristatin PE 24,81,82 ILX651 26,83 LU103 793 2 7,84-86 and dolastatin 15 28.87

7.04.2.1.2.2 Cryptophycins

The cryptophycins are a family of potent antimitotic depsipeptides isolated in the early 1990s from both Nostoc sp. ATCC 53 78988 and N. sp. GSV 224.89 The correct structures of the cryptophycins were determined via total synthesis.90 Although initially identified as antifungal agents, these depsipeptides also inhibit mitosis by binding at the peptide site within the vinca domain and are active against a number of human cancer cell lines, including cell lines resistant to other agents, with IC50 values in the low picomolar range.91-94 The extraordinary potency of the cryptophycins resulted in intense efforts to generate therapeutic analogs from both total and semisynthesis.95-100 An overview of the resulting SAR is depicted in Figure 9.

Lactam ACTIVE

Acyclic methylesters ABOLISH activity

Lactam ACTIVE

Acyclic methylesters ABOLISH activity

Figure 9 Cryptophycin SAR.

Lose 10 Pounds Naturally

Lose 10 Pounds Naturally

Studies show obesity may soon overtake tobacco as the leading cause of death in America. Are you ready to drop those extra pounds you've been carrying around? Awesome. Let's start off with a couple positive don't. You don't need to jump on a diet craze and you don't need to start exercising for hours each day.

Get My Free Ebook


Post a comment