ABSTRACT
BACKGROUND: During the past decade, Taxol has assumed an important role in cancer chemotherapy. The search for novel compounds with a mechanism of action similar to that of Taxol, but with greater efficacy particularly in Taxol-resistant cells, has led to the isolation of new natural products. One such compound, (+)-discodermolide, although structurally distinct from Taxol, has a similar ability to stabilize microtubules. In addition, (+)-discodermolide is active in Taxol-resistant cell lines that overexpress P-glycoprotein, the multidrug-resistant transporter. Interestingly, (+)-discodermolide demonstrates a profound enhancement of the initiation process of microtubule polymerization compared to Taxol. RESULTS: The synthesis of (+)-discodermolide analogs exploiting our highly efficient, triply convergent approach has permitted structure-activity relationship (SAR) studies. Small changes to the (+)-discodermolide structure resulted in a dramatic decrease in the ability of all four discodermolide analogs to initiate tubulin polymerization. Two of the analogs also demonstrated a decrease in total tubulin polymerization, while a change in the olefin geometry at the C8 position produced a significant decrease in cytotoxic activity. CONCLUSIONS: The availability of (+)-discodermolide and the analogs, and the resultant SAR analysis, have permitted an exploration of the similarities and differences between (+)-discodermolide and Taxol. Docking of the X-ray/solution structure of (+)-discodermolide into the Taxol binding site of beta-tubulin revealed two possible binding modes (models I and II). The preferred pharmacophore model (I), in which the C19 side chain of (+)-discodermolide matches with the C2 benzoyl group of Taxol and the delta-lactone ring of (+)-discodermolide overlays with the C13 side chain of Taxol, concurred with the results of the SAR analysis.
Subject(s)
Alkanes , Antineoplastic Agents, Phytogenic/pharmacology , Carbamates , Lactones/pharmacology , Paclitaxel/pharmacology , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Binding, Competitive , Flow Cytometry , Humans , Inhibitory Concentration 50 , Lactones/chemical synthesis , Lactones/chemistry , Microscopy, Electron , Microscopy, Fluorescence , Microtubules/drug effects , Models, Molecular , Paclitaxel/chemistry , Pyrones , Stereoisomerism , Structure-Activity Relationship , Tubulin/drug effects , Tumor Cells, CulturedABSTRACT
[formula: see text] A triply convergent, highly efficient second-generation synthesis of the potent antimitotic agent (+)-discodermolide (1) has been achieved on a 1-g scale.
Subject(s)
Alkanes , Antineoplastic Agents/chemical synthesis , Carbamates , Lactones/chemical synthesis , Animals , Indicators and Reagents , Porifera/chemistry , Pyrones , StereoisomerismABSTRACT
[formula: see text] In this, the second of two Letters, we describe the efficient assembly of (+)-4, a C(20-28) subtarget for the total synthesis of phorboxazoles A (1) and B (2). The synthesis was achieved in 12 linear steps (20% overall yield) via Petasis-Ferrier rearrangement of an E/Z mixture of trisubstituted enol ethers (15) to assemble the C(22-26) cis-tetrahydropyran. A mechanism for the observed diastereoconvergence of 15 is proposed. In addition, a new tactic for the synthesis of enol ethers (e.g., 15) based on the elegant work of Julia is described.
