Total synthesis and biological evaluation of a series of macrocyclic hybrids and analogues of the antimitotic natural products dictyostatin, discodermolide, and taxol - PubMed (original) (raw)

Total synthesis and biological evaluation of a series of macrocyclic hybrids and analogues of the antimitotic natural products dictyostatin, discodermolide, and taxol

Ian Paterson et al. Chem Asian J. 2011.

Abstract

The design, synthesis, and biological evaluation of a series of hybrids and analogues of the microtubule-stabilizing anticancer agents dictyostatin, discodermolide, and taxol is described. A 22-membered macrolide scaffold was prepared by adapting earlier synthetic routes directed towards dictyostatin and discodermolide, taking advantage of the distinctive structural and stereochemical similarities between these two polyketide-derived marine natural products. Initial endeavors towards accessing novel discodermolide/dictyostatin hybrids led to the adoption of a late-stage diversification strategy and the construction of a small library of methyl-ether derivatives, along with the first triple hybrids bearing the side-chain of taxol or taxotere attached through an ester linkage. Biological assays of the anti-proliferative activity of these compounds in a series of human cancer cell lines, including the taxol-resistant NCI/ADR-Res cell line, allowed the proposal of various structure-activity relationships. This led to the identification of a potent macrocyclic discodermolide/dictyostatin hybrid 12 and its C9 methoxy derivative 38, accessible by an efficient total synthesis and with a similar biological profile to dictyostatin.

Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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Figures

Figure 1

Figure 1

Microtubule-stabilising agents Taxol (paclitaxel, 1), Taxotere (docetaxel, 2), discodermolide (3) and dictyostatin (4).

Figure 2

Figure 2

The lowest energy conformer of discodermolide in D2O as deduced by Canales et al This hairpin conformation is broadly similar to the single-crystal X-ray structure of discodermolide in the solid state.

Figure 3

Figure 3

The microtubule-bound bioactive conformations of discodermolide (green) and dictyostatin (blue) overlaid at the taxoid binding site on β-tubulin, as calculated with AutoDock by Canales et al (Image 1). In Image 2, taxol (red) has also been included, the additional region of the binding pocket exploited by the C13 ester side chain can be distinguished.

Figure 4

Figure 4

Representations of C1–C24 and C1–C26 carbon chains of discodermolide (3) and dictyostatin (4) drawn in a linear manner to allow comparison of the matching stereochemistry and structural features.

Figure 5

Figure 5

Reduced derivatives of discodermolide with various levels of saturation (19, 20 and 21) and structures of 10,11-dihydro analogues 22 and 23 of dictyostatin and hybrid 12 respectively.

Figure 6

Figure 6

(Graphs) Cell cycle analysis by flow cytometry of PANC-1 cells incubated for 24 h with DMSO (control), 100 nM dictyostatin/discodermolide hybrid 12 or 9-methoxy derivative 38. Histograms represent samples of approximately 1 × 104 cells per test and are plotted as percentage (_y_-axis) vs stage of cell cycle (_x_-axis). Both compounds result in an accumulation of cells in the G2/M phase. (Images) Immunofluorescence images of PANC-1 cells stained with anti-α-tubulin (green) and propidium iodide (red) and observed with confocal microscopy. Cells were exposed to DMSO (control), 100 nM 12 or 100 nM 38. Dense microtubule bundling can be seen around the nuclei on treatment with 12 and 38, a characteristic feature of microtubule-stabilising agents.

Scheme 1

Scheme 1

Retrosynthetic analysis of dictyostatin/discodermolide hybrid 5.

Scheme 2

Scheme 2

Generation of aldol adduct 10. a) BCl3·DMS, CH2Cl2, −78 → 0 °C, 2 h; b) TEMPO, PhI(OAc)2, CH2Cl2, 20 °C, 2 h; c) K2CO3, 18-crown-6, methyl-_P, P, bis_-(2,2,2-trifluoroethyl)phosphonoacetate, PhMe / HMPA, 0 °C, 16 h; d) 1. 6, Et3N, _c_-Hex2BCl, Et2O, 0 °C, 1 h; 7, −78 °C, 15 min; 2. pH 7 buffer (>95 : 5 dr, 48%). DMS = dimethyl sulfide; HMPA = hexamethylphosphoramide.

Scheme 3

Scheme 3

Completion of dictyostatin/discodermolide hybrid 5. a) (R)-CBS, BH3·THF, CH2Cl2, 0 °C, 3 h; b) cat. PPTS, (MeO)2CMe2, 20 °C, 2 h; c) DDQ, CH2Cl2 / pH 7 buffer, 20 °C, 3 h; d) cat. TEMPO, PhI(OAc)2, CH2Cl2, 0 → 20 °C, 1 h; e) NaClO2, NaH2PO4, 2-methyl-2-butene, _t_BuOH / H2O, 20 °C, 4 h; f) 2,4,6-trichlorobenzoylchloride, Et3N, PhMe, 20 °C, 40 min; DMAP, 20 °C, 20 min; g) 3N HCl, MeOH, 0 → 20 °C, 8 h. CBS = Corey-Bakshi-Shibata catalyst; PPTS = pyridinium _para_-toluenesulfonic acid; DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; TEMPO = 2,2,6,6-tetramethylpiperidine-1-oxy radical; DMAP = 4-dimethylaminopyridine.

Scheme 4

Scheme 4

Retrosynthesis of dictyostatin/discodermolide hybrid 12, leading to fragments 13, 14 and 15.

Scheme 5

Scheme 5

Endgame leading to dictyostatin/discodermolide hybrid 12 and acetonide 18. a) 14, K2CO3, 18-crown-6, PhMe / HMPA, 0 °C, 7 d; b) DDQ, CH2Cl2 / pH 7 buffer, 0 °C, 2.5 h; c) (R)-CBS, BH3· THF, THF, −30 °C, 36 h; d) PPTS, (MeO)2CMe2, CH2Cl2, 0 → 20 °C, 16 h; e) 1. 15, CuTC, NMP, 20 °C, 16 h; 2. KF, MeOH / THF, 20 °C, 90 min; f) 2,4,6-trichlorobenzoylchloride, Et3N, PhMe, 20 °C, 1 h; DMAP, 20 °C, 4 d; g) 3N HCl, MeOH, 0 → 20 °C, 16 h; h) PPTS, (MeO)2CMe2, 0 → 20 °C, 16 h. CuTC = copper(I)-thiophene-2-carboxylate; NMP =_N_-methylpyrrolidinone.

Scheme 6

Scheme 6

Completion of 10,11-dihydro dictyostatin/discodermolide hybrid 23. a) [PPh3CuH]6, PhMe / H2O, 20 °C, 16 h; b) DDQ, CH2Cl2 / pH 7 buffer, 0 °C, 2.5 h; c) Me4NBH(OAc)3, MeCN / THF, 0 °C, 16 h; d) PPTS, (MeO)2CMe2, CH2Cl2, 0 → 20 °C, 16 h; e) 1. 15, CuTC, NMP, 20 °C, 16 h; 2. KF, MeOH / THF, 20 °C, 2 h; f) 2,4,6-trichlorobenzoylchloride, Et3N, PhMe, 20 °C, 1 h; DMAP, 20 °C, 1 d; g) 3N HCl, MeOH, 0 → 20 °C, 16 h.

Scheme 7

Scheme 7

Generation of triple hybrids 31–34. a) PPTS, MeOH / CH2Cl2, 0 → 20 °C, 16 h; b) NaHMDS, THF, −78 °C, 10 min; 29 or 30, −78 → 0 °C, 30 min; c) HF·py, pyridine, THF, 0 → 20 °C, 3 d. NaHMDS = sodium hexamethyldisilazide.

Scheme 8

Scheme 8

Synthesis of C9-methoxy analogues 36 and 38–40. a) Me3O·BF4, Proton Sponge, CH2Cl2, 20 °C, 70 min; b) Me3O·BF4, Proton Sponge, CH2Cl2, 20 °C, 45 min; c) 3N HCl, MeOH, 0 → 20 °C, 16 h; d) HF·py, pyridine, THF, 0 → 20 °C, 3 d. e) NaHMDS, THF, −78 °C, 10 min; 29 or 30, −78 → 0 °C, 30 min; f) HF·py, pyridine, THF, 0 → 20 °C, 3 d.

Scheme 9

Scheme 9

Completion of C7-methoxy analogues 44–46. a) TESOTf, 2,6-lutidine, CH2Cl2, −98 °C, 90 min; b) PPTS, MeOH / CH2Cl2, 0 → 20 °C, 2 h; c) Me3O·BF4, Proton Sponge, CH2Cl2, 20 °C, 90 min; d) PPTS, MeOH / CH2Cl2, 0 → 20 °C, 2 h; e) HF·py, pyridine, THF, 0 → 20 °C, 3 d; f) NaHMDS, THF, −78 °C, 10 min; 29 or 30, −78 → 0 °C; g) HF·py, pyridine, THF, 0 → 20 °C, 3 d. TESOTf = triethylsilyl trifluoromethanesulfonate.

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