Everything about Discodermolide totally explained
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(+)-Discodermolide is a recently discovered
polyketide natural product found to be a potent inhibitor of
tumor cell growth. The molecule's carbon skeleton is made up of eight poly
propionate and four
acetate units with 13 stereocenters.
History
Discodermolide was first isolated in
1990 from the Caribbean marine sponge
Discodermia dissoluta by chemist Dr. Sarath Gunasekera and biologist Dr. Ross Longley, scientists at the
Harbor Branch Oceanographic Institution. The sponge contained 0.002% of discodermolide (7 mg/434 g of sponge). Since the compound is light-sensitive, the sponge must be harvested at a minimum depth of 33 meters. Discodermolide was initially found to have
immunosuppressive and
antifungal activities.
Mechanism of action
Discodermolide has been shown to inhibit the proliferation of human cells by arresting the
cell cycle in
G2- and
M-phase. It hyper-stabilizes
microtubules, especially prevalent during
cell division. Hyper-stabilization of the
mitotic spindle causes cell cycle arrest and cell death by
apoptosis. Over a variety of cell lines, activity has been measured at IC
50 = 3-80 nM.
Discodermolide competes with
paclitaxel for microtubule binding, but with higher affinity and is also effective in in paclitaxel- and
epothilone-resistant cancer cells.
Total syntheses
Several
total syntheses have been published to date by Schreiber, Smith, Paterson, Marshall, and Myles. A review of the various synthetic approaches has also been published.
Clinical development
The
Harbor Branch Oceanographic Institution licensed (+)-discodermolide to
Novartis, which began a phase 1
clinical trial in 2004. Patient accrual was halted due to drug toxicitiy. The
Amos B. Smith's research group
(in collaboration with
Kosan Biosciences) has a preclinical drug development program ongoing.
The compound supply necessary for complete clinical trials can't be met by harvesting, isolation, and purification. As of
2005, attempts at synthesis or semi-synthesis by
fermentation have proven unsuccessful. As a result, all discodermolide used in preclinical studies and clinical trials has come from large-scale total synthesis.
Further Information
Get more info on 'Discodermolide'.
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