Epothilons A and B: Antifungal and Cytotoxic Compounds from Sorangium cellulosum (Myxobacteria). Production, Physico-chemical and Biological Properties.

Gerth, Klaus; Bedorf, Norbert; Höfle, Gerhard; Irschik, Herbert; Reichenbach, Hans

doi:10.7164/antibiotics.49.560

Cited by 618 publications

(367 citation statements)

References 4 publications

Supporting

Mentioning

359

Contrasting

Unclassified

Order By: Relevance

“…3 Epothilones are 16-membered macrolides isolated from the myxobacterium Sorangium cellulosum. 4,5 These compounds were originally described as antifungal agents, however, their use was limited because of an associated herbicidal activity. The tumor cytotoxicity of these drugs was revealed when they were tested in the NCI 60-cell line screen.…”

Section: Introductionmentioning

confidence: 99%

“…Epothilones inhibited the growth of a variety of human tumor cell lines with an IC 50 in the 100 pM range. 4,6,7 The mechanism whereby epothilones exert their cellular effects is similar to that of paclitaxel. 6,7 Epothilones bind to tubulin and cause the hyperstabilization of microtubules with subsequent mitotic arrest and apoptotic cell death.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The microtubule-stabilizing agents epothilones A and B and their desoxy-derivatives induce mitotic arrest and apoptosis in human prostate cancer cells

Sepp‐Lorenzino

Balog

et al. 1999

Prostate Cancer Prostatic Dis

View full text Add to dashboard Cite

Epothilones are a new class of natural products that bind to tubulin and prevent the depolymerization of microtubules, although they have no structural similarity to paclitaxel. Taxanes are only marginally effective in the treatment of disseminated prostate cancer, although they may have useful activity when administered in combination with estramustine. Unlike paclitaxel, epothilones are not substrates for P-glycoprotein and are active in multidrug resistant cells. Epothilones A and B (EA, EB) have recently been synthesized in toto. In this report, we examine the effects of synthetic epothilones and their desoxy derivatives, as well as paclitaxel, on prostate cancer cell lines. EB was the most active of these compounds in tissue culture (IC 50 : 50 ± 75 pM), four to ten-fold more potent than paclitaxel. EA and the desoxyderivatives of EA and EB (dEA, dEB) were also active, but less potent than EB. Each of these compounds causes mitotic block followed by apoptotic cell death. The relative potencies for cell cycle arrest and cytotoxicity directly correlate with the ability of the drugs to bind microtubules, stabilize mitotic spindles and induce the formation of interphase microtubule bundles. Therefore, synthetic epothilones are potent inhibitors of prostate cancer cell lines and work in a fashion similar to paclitaxel. Recently, we showed that farnesyl transferase inhibitors sensitize tumor cells to paclitaxelinduced mitotic arrest. We now have extended these observations to show that paclitaxel and the epothilones synergize with FTI to arrest the growth of prostate cancer cells. Moreover, this occurs in DU145, a cell line that is not particularly sensitive to the FTI. The combination of FTI and epothilone represent a new potential clinical strategy for the treatment of advanced prostatic cancer.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The microtubule-stabilizing agents epothilones A and B and their desoxy-derivatives induce mitotic arrest and apoptosis in human prostate cancer cells

Sepp‐Lorenzino

Balog

et al. 1999

Prostate Cancer Prostatic Dis

View full text Add to dashboard Cite

show abstract

“…Gene clusters are involved in every step of the production of biologically active polyketides 160 , and manipulating the biosynthetic gene clusters can allow more economical and efficient production of chirally pure polyketide compounds 161 . Two examples, epitholone 162 and lomaiviticin 163 , are presented in Figure 3.…”

Section: Applyingmentioning

confidence: 99%

The re-emergence of natural products for drug discovery in the genomics era

Harvey

Edrada-Ebel

Quinn

2015

Nat Rev Drug Discov

2,112

1,410

View full text Add to dashboard Cite

Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review advances in chemical techniques for the isolation and structural elucidation of natural products that have reduced these technological barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery.

show abstract

“…[1][2][3][4][5][6] The epothilones are obtained from the fermentation broth of the cellulose-degrading myxobacterium, Sorangium cellulosum. 7 These natural products are polyketide-derived, 16-membered ring macrolides. ixabepilone [1S-[1R*, 3R* (E), 7R*, 10S*, 12R*, 16S*]]-7,11-dihydroxy-8, 8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl) ethenyl]-17-oxa-4-azabicylo [14.1.0] heptadecane-5, 9-dione is a semisynthetic derivative of epothilone B in which the macrolide ring oxygen atom has been replaced with a nitrogen atom to give the corresponding macrolactam.…”

mentioning

confidence: 99%

A Phase I clinical trial of ixabepilone (BMS‐247550), an epothilone B analog, administered intravenously on a daily schedule for 3 days

Zhuang

Agrawal

Edgerly

et al. 2005

Cancer

View full text Add to dashboard Cite

BACKGROUNDThe epothilones are a novel class of microtubule‐stabilizing agents. Ixabepilone (BMS‐247550; NSC 710428) is a semisynthetic analog of the natural product epothilone B. The authors conducted a Phase I study by administering ixabepilone to patients as a 1‐hour intravenous infusion daily for 3 consecutive days every 21 days.METHODSTwenty‐six patients were enrolled and received ixabepilone at a starting dose of 8 or 10 mg/m2 per day for 3 consecutive days.RESULTSOne hundred and nineteen cycles were administered to 26 patients. The maximum‐tolerated dose was 8 mg/m2 per day of ixabepilone administered as a 1‐hour intravenous infusion daily for 3 consecutive days every 21 days. The dose‐limiting toxicity (DLT) was neutropenia. Other nonhematologic Grade 3 toxicities included fatigue (3 cycles), hyponatremia (1 cycle), anorexia (1 cycle), ileus (1 cycle), stomatitis (1 cycle), and emesis (1 cycle). Prolonged disease stabilization was observed in patients with mesothelioma, ovarian carcinoma, and renal cell carcinoma.CONCLUSIONSThe recommended Phase II dose of ixabepilone on the daily schedule for 3 days was 8–10 mg/m2 per day. Neutropenia was the DLT. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting. Cancer 2005. Published 2005 by the American Cancer Society.

show abstract

Epothilons A and B: Antifungal and Cytotoxic Compounds from Sorangium cellulosum (Myxobacteria). Production, Physico-chemical and Biological Properties.

Cited by 618 publications

References 4 publications

The microtubule-stabilizing agents epothilones A and B and their desoxy-derivatives induce mitotic arrest and apoptosis in human prostate cancer cells

The microtubule-stabilizing agents epothilones A and B and their desoxy-derivatives induce mitotic arrest and apoptosis in human prostate cancer cells

The re-emergence of natural products for drug discovery in the genomics era

A Phase I clinical trial of ixabepilone (BMS‐247550), an epothilone B analog, administered intravenously on a daily schedule for 3 days

Contact Info

Product

Resources

About