Limits...
Zampanolide and dactylolide: cytotoxic tubulin-assembly agents and promising anticancer leads.

Chen QH, Kingston DG - Nat Prod Rep (2014)

Bottom Line: Zampanolide is a marine natural macrolide and a recent addition to the family of microtubule-stabilizing cytotoxic agents.Zampanolide exhibits unique effects on tubulin assembly and is more potent than paclitaxel against several multi-drug resistant cancer cell lines.A high-resolution crystal structure of αβ-tubulin in complex with zampanolide explains how taxane-site microtubule-stabilizing agents promote microtubule assemble and stability.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA. qchen@csufresno.edu.

ABSTRACT
Zampanolide is a marine natural macrolide and a recent addition to the family of microtubule-stabilizing cytotoxic agents. Zampanolide exhibits unique effects on tubulin assembly and is more potent than paclitaxel against several multi-drug resistant cancer cell lines. A high-resolution crystal structure of αβ-tubulin in complex with zampanolide explains how taxane-site microtubule-stabilizing agents promote microtubule assemble and stability. This review provides an overview of current developments of zampanolide and its related but less potent analogue dactylolide, covering their natural sources and isolation, structure and conformation, cytotoxic potential, structure-activity studies, mechanism of action, and syntheses.

Show MeSH

Related in: MedlinePlus

Porco's synthesis of the macrolactone core of (–)-zampanolide.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4126874&req=5

sch25: Porco's synthesis of the macrolactone core of (–)-zampanolide.

Mentions: Porco's synthesis of the macrocyclic core of 1 was initiated by interest in the N-acyl hemiaminal side chain and its apparent stabilization through an intramolecular hydrogen bond network, and entailed preparation of an N-acyl hemiaminal model system.58,59 The synthetic strategy is characterised by construction of fragment C15–C20 by a one-pot reduction/vinylogous aldol reaction, construction of the 2,6-cis-THP through an intramolecular silyl-modified Sakurai (ISMS) reaction,60 and closing the macrolactone ring via an sp2–sp3 Stille reaction. As outlined in Scheme 23, Porco's synthetic strategy for zampanolide is to install the N-acyl hemiaminal side chain from the protected amino alcohol-bearing macrolide 108 at a late stage using their previously reported oxidative decarboxylation–hydrolysis approach.59 In order to install the potentially sensitive 1,3-dienoate portion of the macrolide at a late stage, these workers investigated a less conventional disconnection by targeting 1,4-dienoate 109 instead of 1,3-dienoate 108. They expected that subsequent isomerization would occur under macrocyclic control and installation of the dienoate in a “masked” format would allow for unveiling after construction of the macrolide. Further disconnection of macrolide 109 afforded three precursors: β-stannylacrylic acid 110, allylic acetate 111, and the pyran containing the C7–C20 fragment 112. The C3–C4 bond would be constructed via an intramolecular Stille reaction, representing a pioneer example of using an sp2–sp3 Stille macrocyclization in a complex synthesis. Synthesis of the C7–C20 fragment is shown in Scheme 24. The two-step process developed by Kiyooka61 using DIBAL-H and TiCl2(O-iPr)2 provided the desired vinylogous aldol product 115 (dr = 16 : 1) from methyl ester 113. Vinylogous aldol substrate 115 was next advanced to the α,β-unsaturated aldehyde 116 through a three-step sequence including protection of amino alcohol as the N,O-acetonide, reduction of the methyl ester, and subsequent oxidation with Bobbit's reagent.62 The requisite allylsilane 119 for an intramolecular Sakurai cyclisation (IMSC)60 reaction was obtained from Cu(i)-mediated addition of vinyl Grignard reagent 118 (ref. 63) to chiral epoxide 117 (ref. 64) (Scheme 24). The IMSC reaction of 116 and 119 mediated by Bi(OTf)3 in conjunction with 2,6-di-tert-butylpyridine as triflic acid scavenger afforded pyran 120 as a single diastereomer. Elaboration of the terminal olefin by Grubbs–Hoveyda cross-metathesis provided α,β-unsaturated aldehyde 112 (Scheme 24). Allylation of 112 with the Trost trimethylenemethane (TMM) reagent 111 (ref. 65) in the presence of BnOTMS afforded allylic acetate 121 (dr = 1 : 1) (Scheme 25). Removal of the acetonide protecting group followed by esterification with β-stannyl acrylate 110 (ref. 66) provided the macrocyclization precursor 122. Macrocyclization of vinylstannane 122 was mediated by Pd(PPh3)4-Bu4NI-DIEA to afford macrolactone 109. Porco indicated that only 1,4-diene product was observed, likely due to the constraints of the macrolide on olefin isomerization. Subsequent isomerization by DBU resulted in formation of 1,3-diene 108 in quantitative yield as a 1 : 1 mixture of E,Z-isomers.


Zampanolide and dactylolide: cytotoxic tubulin-assembly agents and promising anticancer leads.

Chen QH, Kingston DG - Nat Prod Rep (2014)

Porco's synthesis of the macrolactone core of (–)-zampanolide.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126874&req=5

sch25: Porco's synthesis of the macrolactone core of (–)-zampanolide.
Mentions: Porco's synthesis of the macrocyclic core of 1 was initiated by interest in the N-acyl hemiaminal side chain and its apparent stabilization through an intramolecular hydrogen bond network, and entailed preparation of an N-acyl hemiaminal model system.58,59 The synthetic strategy is characterised by construction of fragment C15–C20 by a one-pot reduction/vinylogous aldol reaction, construction of the 2,6-cis-THP through an intramolecular silyl-modified Sakurai (ISMS) reaction,60 and closing the macrolactone ring via an sp2–sp3 Stille reaction. As outlined in Scheme 23, Porco's synthetic strategy for zampanolide is to install the N-acyl hemiaminal side chain from the protected amino alcohol-bearing macrolide 108 at a late stage using their previously reported oxidative decarboxylation–hydrolysis approach.59 In order to install the potentially sensitive 1,3-dienoate portion of the macrolide at a late stage, these workers investigated a less conventional disconnection by targeting 1,4-dienoate 109 instead of 1,3-dienoate 108. They expected that subsequent isomerization would occur under macrocyclic control and installation of the dienoate in a “masked” format would allow for unveiling after construction of the macrolide. Further disconnection of macrolide 109 afforded three precursors: β-stannylacrylic acid 110, allylic acetate 111, and the pyran containing the C7–C20 fragment 112. The C3–C4 bond would be constructed via an intramolecular Stille reaction, representing a pioneer example of using an sp2–sp3 Stille macrocyclization in a complex synthesis. Synthesis of the C7–C20 fragment is shown in Scheme 24. The two-step process developed by Kiyooka61 using DIBAL-H and TiCl2(O-iPr)2 provided the desired vinylogous aldol product 115 (dr = 16 : 1) from methyl ester 113. Vinylogous aldol substrate 115 was next advanced to the α,β-unsaturated aldehyde 116 through a three-step sequence including protection of amino alcohol as the N,O-acetonide, reduction of the methyl ester, and subsequent oxidation with Bobbit's reagent.62 The requisite allylsilane 119 for an intramolecular Sakurai cyclisation (IMSC)60 reaction was obtained from Cu(i)-mediated addition of vinyl Grignard reagent 118 (ref. 63) to chiral epoxide 117 (ref. 64) (Scheme 24). The IMSC reaction of 116 and 119 mediated by Bi(OTf)3 in conjunction with 2,6-di-tert-butylpyridine as triflic acid scavenger afforded pyran 120 as a single diastereomer. Elaboration of the terminal olefin by Grubbs–Hoveyda cross-metathesis provided α,β-unsaturated aldehyde 112 (Scheme 24). Allylation of 112 with the Trost trimethylenemethane (TMM) reagent 111 (ref. 65) in the presence of BnOTMS afforded allylic acetate 121 (dr = 1 : 1) (Scheme 25). Removal of the acetonide protecting group followed by esterification with β-stannyl acrylate 110 (ref. 66) provided the macrocyclization precursor 122. Macrocyclization of vinylstannane 122 was mediated by Pd(PPh3)4-Bu4NI-DIEA to afford macrolactone 109. Porco indicated that only 1,4-diene product was observed, likely due to the constraints of the macrolide on olefin isomerization. Subsequent isomerization by DBU resulted in formation of 1,3-diene 108 in quantitative yield as a 1 : 1 mixture of E,Z-isomers.

Bottom Line: Zampanolide is a marine natural macrolide and a recent addition to the family of microtubule-stabilizing cytotoxic agents.Zampanolide exhibits unique effects on tubulin assembly and is more potent than paclitaxel against several multi-drug resistant cancer cell lines.A high-resolution crystal structure of αβ-tubulin in complex with zampanolide explains how taxane-site microtubule-stabilizing agents promote microtubule assemble and stability.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA. qchen@csufresno.edu.

ABSTRACT
Zampanolide is a marine natural macrolide and a recent addition to the family of microtubule-stabilizing cytotoxic agents. Zampanolide exhibits unique effects on tubulin assembly and is more potent than paclitaxel against several multi-drug resistant cancer cell lines. A high-resolution crystal structure of αβ-tubulin in complex with zampanolide explains how taxane-site microtubule-stabilizing agents promote microtubule assemble and stability. This review provides an overview of current developments of zampanolide and its related but less potent analogue dactylolide, covering their natural sources and isolation, structure and conformation, cytotoxic potential, structure-activity studies, mechanism of action, and syntheses.

Show MeSH
Related in: MedlinePlus