The cryptophycins: Their synthesis and anticancer activity

Eggen, MariJean; Georg, Gunda I.

doi:10.1002/med.10002

Cited by 90 publications

(74 citation statements)

References 51 publications

(80 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The β-epoxide functional group in cryptophycin natural products is crucial for biological activity, 14 and relates directly to their promising anti-cancer activity. In this study, we have demonstrated that the CrpE P450 catalyzes efficient, stereospecific introduction of the functional group and provides a possible alternative to current chemical methods.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Cryptophycin P450 Epoxidase Reveals Substrate Tolerance and Cooperativity

et al. 2008

View full text Add to dashboard Cite

Cryptophycins are potent anticancer agents isolated from Nostoc sp. ATCC 53789 and Nostoc sp. GSV 224. The most potent natural cryptophycin analogues retain a β-epoxide at the C2′-C3′ position of the molecule. A P450 epoxidase encoded by crpE recently identified from the cryptophycin gene cluster was shown to install this key functional group into cryptophycin-4 (Cr-4) to produce cryptophycin-2 (Cr-2) in a regio-and stereospecific manner. Here we report a detailed characterization of the CrpE epoxidase using an engineered maltose binding protein (MBP)-CrpE fusion. The substrate tolerance of the CrpE polypeptide was investigated with a series of structurally related cryptophycin analogues generated by chemoenzymatic synthesis. The enzyme specifically installed a β-epoxide between C2′ and C3′ of cyclic cryptophycin analogues. The k cat /K m values of the enzyme were determined to provide further insights into the P450 epoxidase catalytic efficiency affected by substrate structural variation. Finally, binding analysis revealed cooperativity of MBP-CrpE toward natural and unnatural desepoxy cryptophycin substrates.

show abstract

Section: Discussionmentioning

confidence: 99%

Analysis of the Cryptophycin P450 Epoxidase Reveals Substrate Tolerance and Cooperativity

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Establishing this epoxide in the desired ␤-stereochemistry was a challenge and required several synthetic steps (23,24). The characterization of this enzyme allowed the first stereospecific synthesis of cryptophycin 2 through a chemoenzymatic synthesis via seco-cryptophycin 4 involving two enzymes, the thioesterase from CrpD and CrpE.…”

Section: Rohrmentioning

confidence: 99%

Cryptophycin Anticancer Drugs Revisited

Rohr

2006

ACS Chem. Biol.

View full text Add to dashboard Cite

magine a new biotechnologically producible anticancer drug of marine origin with a tubulin-destabilizing mechanism of action that is not negatively affected by P-glycoprotein, a commonly used efflux system of resistant cancer cell lines. This would add another unique natural product into the armamentarium of cancer chemotherapeutics and justify the tremendous efforts that have been invested into marine drug discovery efforts over the past decade or so. The cryptophycins (e.g., cryptophycin 1; Figure 1, panel a) are among the most promising candidates for such a new drug. Like many other natural products, several of marine origin, the cryptophycins interfere with the dynamics of tubulin polymerization and depolymerization. This activity has a long history. Microtubules are dynamic cell structures that play an important role in cell division. Various natural products, such as colchicine, combretastatins, vinca alkaloids, taxanes, epothilones, discodermolides, and dolastatins, bind to tubulin. They eventually cause metaphasic mitotic arrest and consequently apoptotic cell death (1-9). The oldest drug in this context is colchicine. Its damaging effect on tumor vasculature was known in the 1930s, but it was too toxic as an anticancer agent and is now used mostly to treat severe inflammation from gout (10). However, derivatives of the structurally closely related combretastatins A-1 and A-4P were developed and are currently in phase 2 clinical trials as anticancer agents (10). Other tubulin binders, especially several natural (e.g., vincristine and vinblastine) and semisynthetic (e.g., vin-

show abstract

“…[55] Interestingly, the most abundant compound (220 mg cryptophycin 1 were isolated from 50 g algae), was the most cytotoxic entity. The epoxide was essential for activity, as were all structural features of the polyketide fragment.…”

Section: Introductionmentioning

confidence: 99%

Secondary Metabolites from Cyanobacteria: Complex Structures and Powerful Bioactivities

Gademann¹,

Portmann

2008

COC

233

168

View full text Add to dashboard Cite

This review presents natural products from cyanobacteria. Several classes of secondary metabolites are highlighted. Toxic metabolites from these prokaryotic photosynthetic organisms include compounds such as microcystin, anatoxin and saxitoxin, which display hepatotoxicity and neurotoxicity. Their potential as drugs in cancer therapy is discussed based on the cryptophycin class of potent cytotoxic agents. The next part of this review highlights iron chelators from cyanobacteria, including schizokinen, synechobactin and anachelin. The biogenesis of anachelin is investigated as its mechanism of iron acquisition. Several indole alkaloids are then reviewed, from simple carbolines such as bauerines and nostocarboline to complex polycyclic structures such as hapalindole, welwitindolinone and ambiguine. The latter compounds present fascinating structure combined with powerful bioactivities and interesting biogenetic pathways. In the last part, protease inhibitors from cyanobacteria are discussed (cyanopeptolins, micropeptin and oscillapeptin) and their structure/activity relationships and selectivity for trypsin / chymotrypsin are presented. All these examples highlight the large structural variety of cyanobacterial metabolites combined with powerful biological activities. Cyanobacteria can thus be considered a prime source both for novel bioactive compounds and for leads for drugs.

show abstract

The cryptophycins: Their synthesis and anticancer activity

Cited by 90 publications

References 51 publications

Analysis of the Cryptophycin P450 Epoxidase Reveals Substrate Tolerance and Cooperativity

Analysis of the Cryptophycin P450 Epoxidase Reveals Substrate Tolerance and Cooperativity

Cryptophycin Anticancer Drugs Revisited

Secondary Metabolites from Cyanobacteria: Complex Structures and Powerful Bioactivities

Contact Info

Product

Resources

About