The microtubule binding affinities of a series of synthetic taxanes have been measured with the aims of dissecting individual group contributions and obtaining a rationale for the design of novel compounds with the ability to overcome drug resistance. As previously observed for epothilones, the positive and negative contributions of the different substituents to the binding free energies are cu...

Endometrial carcinoma is the most common gynecological malignancy. Prognosis is poor following disease recurrence or diagnosis at an advanced stage. In this setting, combination chemotherapy is the hallmark of therapy. However, women who develop recurrence or metastatic disease after initial treatment have limited options for additional therapy. This emphasizes the need for new treatment approa...

Microtubule stabilizers are powerful antimitotic compounds and represent a proven cancer treatment strategy. Several classes of compounds in clinical use or trials, such as the taxanes and epothilones, bind to the same region of β-tubulin. Determining how these molecules interact with tubulin and stabilize microtubules is important both for understanding the mechanism of action and enhancing ch...

The interactions of epothilone analogs with the paclitaxel binding site of microtubules were studied. The influence of chemical modifications in the C15 side chain and in C12 on binding affinity and microtubule elongation was characterized. Modifications favorable for binding affinity are (1). a thiomethyl group at C21 of the thiazole side chain, (2). a methyl group at C12 in S configuration, (...

Microtubule (MT) stabilizing drugs hold promise as potential treatments for Alzheimer's disease (AD) and related tauopathies. However, thus far epothilone D has been the only brain-penetrant MT-stabilizer to be evaluated in tau transgenic mice and in AD patients. Furthermore, this natural product exhibits potential deficiencies as a drug candidate, including an intravenous route of administrati...

Although microtubule interacting agents inhibit spindle dynamics, thereby leading to a block in mitosis, we report that low concentrations of these drugs result in differential mitotic effects. Microtubule-stabilizing agents including Taxol, epothilone B, and discodermolide produce aneuploid populations of A549 cells in the absence of a mitotic block. Such aneuploid populations are diminished i...

Taxane re-treatment is complicated by: modest and variable efficacy to same5 or different taxane6 b f i d fi i i f “ i ” a sence o str ct e n t on o res stance uncertainty as to impact of disease-free / taxane-free interval on response rate 1NCCN Clinical Practice Guidelines in Oncology, Breast Cancer V.1.2009 2A d l & H t b i J Cli O l 2008 26 3660 2 n reopou ou or o agy , n nco ; : – 3Tan et ...

Recent research on the chemistry of natural products from the author's group that led to the receipt of the ACS Ernest Guenther Award in the Chemistry of Natural Products is reviewed. REDOR NMR and synthetic studies established the T-taxol conformation as the bioactive tubulin-binding conformation, and these results were confirmed by the synthesis of compounds which clearly owed their activity ...