Topic
Cryptophycin 52
About: Cryptophycin 52 is a research topic. Over the lifetime, 30 publications have been published within this topic receiving 1209 citations.
Papers
TL;DR: The convergent total synthesis of cryptophycins C and D is described, showing that in both natural products the absolute configuration of the a-amino acid corresponds to the D-series and correcting the structural assignment for cryptophycin C has been corrected.
Abstract: The convergent total synthesis of cryptophycins C and D is described. It has been shown that in both natural products the absolute configuration of the a-amino acid corresponds to the D-series. The structural assignment for cryptophycin C has been corrected to reflect this fact. Since the structure of cryptophycin A has been correlated to cryptophycin C, the chloro-0-methyltyrosine unit in cryptophycin A has the D-configuration. Cryptophycins are potent tumor-selective cytotoxins associated with the terrestrial blue-green algae Nostoc sp. GSV 224' and Nostoc sp. ATCC 53789.2 The major cytotoxin in each alga, cryptophycin A, shows excellent activity against solid tumors implanted in mice, including a drug-resistant tumor. Over 20 related cytotoxins are present in the GSV 224 strain as minor constituent^,'^^ and some of these compounds, e.g., cryptophycins B and C, have been isolated in sufficient amounts for in vivo e~aluation.~ In order to acquire adequate quantities of selected naturally-occurring cryptophycins and synthetic analogs for structure-activity relationship (SAR) studies, preclinical evaluation, and human clinical trials, we have designed a general synthesis. Cryptophycins C and D, as described in the original paper, were chosen to be the initial targets as they represented examples from both of the alleged Land D-tyrosine series. We report here the total syntheses of cryptophycins C and D which (1) revise the structures of cryptophycins A and C to reflect the D-configuration for the a-amino acid unit as depicted in the structural drawings in this paper and (2) confirm the structures of cryptophycins B and D. Retrosynthetic analysis of the cryptophycins was straightforward: the structure is composed of four units (A-D, Figure 1); consequently several convergent approaches could be envisioned. The combination of two pairs of units (e.g., A-B and C-D) appeared to be optimally convergent. Since the success of the synthesis depended on the formation of a 16membered depsipeptide from an acyclic precursor, a macrolactamization involving the amino group of unit C and the carboxylate of unit B appeared to be the best choice. The acyclic precursor to cryptophycin D would therefore be 1. This, in turn, suggested a disconnection into two fragments, one represented by 2 and composed of (S)-( -)-2-hydroxy-4-methylvaleric (L-leucic) acid (D) and (R)-3-amino-2-methylpropanoic acid (C) units, and the other by 3 and composed of O-methylD-tyrosine (B) and (2E,7E,5S,6R)-5-hydroxy-6-methyl-8-phenyloctadienoic acid (A) units. In the direction of the synthesis, @ Abstract published in Advance ACS Absfracts, February 15, 1995. (1) Trimurtulu, G.; Ohtani, I.; Patterson, G. M. L.; Moore, R. E.; Corbett, T. H.; Valeriote, F. A.; Demchik, L. J. Am. Chem. SOC. 1994, 116, 47294731. (2) Schwartz, R. E.; Hirsch, C. F.; Sesin, D. F.; Flor, J. E.; Chartrain, M.; Fromtling, R. E.; Harris, G. H.; Salvatore, M. J.; Liesch, J. M.; Yudin, K. J. Ind. Microbiol. 1990, 5, 113-24. (3) Trimurtulu, G.; Ogino, J.; Heltzel, C. E.; Patterson, G. M. L.; Moore, R. E. Manuscript in preparation. An explanation of the structural misassignment for cryptophycins A and C is presented. (4) Heltzel, C. E.; Ogino, J.; Trimurtulu, G.; Mooberry, S. L.; Patterson, G. M. L.; Moore, R. E.; Corbett, T. H.; Valeriote, F. A,; Demchik, L. Manuscript in preparation. A Figure 1. Numbering system for each of the units of cryptophycins C and D. This numbering system is used for the NMR data.
185 citations
TL;DR: Cryptophycin 52 failed to produce measurable responses utilizing this schedule, but in 40% of patients there was evidence of disease stabilization, and other schedules of cryptophycin52 should be considered.
118 citations
TL;DR: The data suggest that cryptophycin-52 potently perturbs kinetic events at micro Tubule ends that are required for microtubule function during mitosis and that it acts by forming a reversible cryptophyin-52-tubulin stabilizing cap at microtubules ends.
Abstract: Cryptophycin-52 (LY355703) is a new synthetic member of the cryptophycin family of antimitotic antitumor agents that is currently undergoing clinical evaluation. At high concentrations (≥10 times the IC50), cryptophycin-52 blocked HeLa cell proliferation at mitosis by depolymerizing spindle microtubules and disrupting chromosome organization. However, low concentrations of cryptophycin-52 inhibited cell proliferation at mitosis (IC50 = 11 pM) without significantly altering spindle microtubule mass or organization. Cryptophycin-52 appears to be the most potent suppressor of microtubule dynamics found thus far. It suppressed the dynamic instability behavior of individual microtubules in vitro (IC50 = 20 nM), reducing the rate and extent of shortening and growing without significantly reducing polymer mass or mean microtubule length. Using [3H]cryptophycin-52, we found that the compound bound to microtubule ends in vitro with high affinity (Kd, 47 nM, maximum of ≈19.5 cryptophycin-52 molecules per microtubule). By analyzing the effects of cryptophycin-52 on dynamics in relation to its binding to microtubules, we determined that ≈5–6 molecules of cryptophycin-52 bound to a microtubule were sufficient to decrease dynamicity by 50%. Cryptophycin-52 became concentrated in cells 730-fold, and the resulting intracellular cryptophycin-52 concentration was similar to that required to stabilize microtubule dynamics in vitro. The data suggest that cryptophycin-52 potently perturbs kinetic events at microtubule ends that are required for microtubule function during mitosis and that it acts by forming a reversible cryptophycin-52-tubulin stabilizing cap at microtubule ends.
103 citations
TL;DR: The results suggest that cryptophycin 1 exerts its antiproliferative and antimitotic activity by binding reversibly and with high affinity to the ends of microtubules, perhaps in the form of a tubulin-cryptophycin1 complex, resulting in the most potent suppression ofmicrotubule dynamics yet described.
Abstract: Cryptophycin 1 is a remarkably potent antiproliferative compound that shows excellent antitumor activity against mammary, colon, and pancreatic adenocarcinomas in mouse xenographs. At picomolar concentrations, cryptophycin 1 blocks cells in the G2/M phase of the cell cycle by an apparent action on microtubules. The compound binds to tubulin, inhibits microtubule polymerization, and depolymerizes preformed microtubules in vitro. Its exceptionally powerful antitumor activity (many-fold greater than paclitaxel or the vinca alkaloids) raises important questions about its mechanism of action. By quantitative video microscopy, we examined the effects of cryptophycin 1 on the dynamics of individual microtubules assembled to steady state from bovine brain tubulin. At low nanomolar concentrations, in the absence of net microtubule depolymerization, cryptophycin 1 potently stabilized microtubule dynamics. It reduced the rate and extent of microtubule shortening and growing and increased the frequency of rescue. The results suggest that cryptophycin 1 exerts its antiproliferative and antimitotic activity by binding reversibly and with high affinity to the ends of microtubules, perhaps in the form of a tubulin-cryptophycin 1 complex, resulting in the most potent suppression of microtubule dynamics yet described.
95 citations
TL;DR: An endocyclic trans-amide linkage within the macrocyclic antitumor agent cryptophycin-52 was replaced by a 1,4-disubstituted 1H-1,2,3-triazole ring and macrocyclisation of the triazole analogue was accomplished by macrolactamization as well as by Cu(I)-mediated "click"-cyclization.
86 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2021 | 1 |
| 2010 | 1 |
| 2008 | 1 |
| 2004 | 3 |
| 2003 | 4 |
| 2002 | 4 |