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Recent progress with microtubule stabilizers: new compounds, binding modes and cellular activities.

ABSTRACT: Nature has yielded numerous classes of chemically distinct microtubule stabilizers. Several of these, including paclitaxel (Taxol) and docetaxel (Taxotere), are important drugs used in the treatment of cancer. New microtubule stabilizers and novel formulations of these agents continue to provide advances in cancer therapy. In this review we cover recent progress in the chemistry and biology of these diverse microtubule stabilizers focusing on the wide range of organisms that produce these compounds, their mechanisms of inhibiting microtubule-dependent processes, mechanisms of drug resistance, and their interactions with tubulin including their distinct binding sites and modes. A new potential role for microtubule stabilizers in neurodegenerative diseases is reviewed.

SUBMITTER: Rohena CC

PROVIDER: S-EPMC4167679 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Recent progress with microtubule stabilizers: new compounds, binding modes and cellular activities.

Rohena Cristina C CC Mooberry Susan L SL

Natural product reports 20140301 3

Nature has yielded numerous classes of chemically distinct microtubule stabilizers. Several of these, including paclitaxel (Taxol) and docetaxel (Taxotere), are important drugs used in the treatment of cancer. New microtubule stabilizers and novel formulations of these agents continue to provide advances in cancer therapy. In this review we cover recent progress in the chemistry and biology of these diverse microtubule stabilizers focusing on the wide range of organisms that produce these compou ...[more]

PMID: 24481420

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Project description:This account exemplifies our recent progress on the strategic incorporation of fluorine and organofluorine groups to (i) taxoid anticancer agents, (ii) acylhydrazone-based antifungal agents and (iii) inhibitors of matrix metalloproteinase 9 (MMP9) for medicinal chemistry and chemical biology studies. In the case study (i), a series of next-generation fluorotaxoids, bearing m-OCF3 or m-OCF2H group in the C2-benzoate moiety was designed, synthesized and examined for their potencies. A number of these fluorotaxoids possess two orders of magnitude greater potency in different drug-resistant cancer cell lines as compared to paclitaxel. One of these next-generation fluorotaxoids, SB--121205wasselected for detailed mechanistic study against highly paclitaxel-resistant human breast cancer cell line, MCF-7/PTX, which disclosed a unique mechanism of action. Recently, glucosylceramide (GlcCer) synthesis emerged as a promising target for next-generation antifungal agents, especially against cryptococcosis, candidiasis and pulmonary aspergillosis. The HTP screening of compound libraries identified several acylhydrazones as hit compounds. In the case study (ii), fluoro-acylhydrazones containing F, OCF3, OCHF2, o-F/p-OCF3, as well as o-F/p-CF3 functional groups in the ring A and ring B were designed based on these hit compounds, synthesized and examined for their potencies against C. neoformans. A number of those novel fluoro-acylhydrazones exhibited high potency and excellent killing properties. The hemopexin-like domain of matrix metalloproteinases (MMPs) is a highly promising target to circumvent the critical issue in the development of MMP inhibitors for the treatment of various cancers. In the case study (iii), a small optimization library of compounds, based on the OCHF2-containing hit compound, SB-M-001, was generated and evaluated, which identified a fluorine-containing new lead compound, SB-M-103. SB-M-103 was found to inhibit tumor cell growth, migration, and invasion by effectively disrupting the MMP-9 homodimerization.

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Recent progress with microtubule stabilizers: new compounds, binding modes and cellular activities.

Publications

Recent progress with microtubule stabilizers: new compounds, binding modes and cellular activities.

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