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. 2015 Dec 28;13(48):11633-44.
doi: 10.1039/c5ob01882j. Epub 2015 Oct 15.

Complementary isonitrile-based multicomponent reactions for the synthesis of diversified cytotoxic hemiasterlin analogues

Giordano Lesma  1 , Ivan Bassanini, Roberta Bortolozzi, Chiara Colletto, Ruoli Bai, Ernest Hamel, Fiorella Meneghetti, Giulia Rainoldi, Mattia Stucchi, Alessandro Sacchetti, Alessandra Silvani, Giampietro Viola
Affiliations

Complementary isonitrile-based multicomponent reactions for the synthesis of diversified cytotoxic hemiasterlin analogues

Giordano Lesma et al. Org Biomol Chem. .

Abstract

A small family of structural analogues of the antimitotic tripeptides, hemiasterlins, have been designed and synthesized as potential inhibitors of tubulin polymerization. The effectiveness of a multicomponent approach was fully demonstrated by applying complementary versions of the isocyanide-based Ugi reaction. Compounds strictly related to the lead natural products, as well as more extensively modified analogues, have been synthesized in a concise and convergent manner. In some cases, biological evaluation provided evidence for strong cytotoxic activity (six human tumor cell lines) and for potent inhibition of tubulin polymerization.

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Figures

Fig. 1
Fig. 1
Tubulin polymerization inhibitors: natural hemiasterlins and synthetic analogues.
Fig. 2
Fig. 2
Structures of hemiasterlin analogues 5–12.
Fig. 3
Fig. 3
ORTEP19 view of compound 18b, anti (R,S), and the relative atom-numbering scheme (thermal ellipsoids at 40% probability).
Fig. 4
Fig. 4
Percentage of cells in each phase of the cell cycle in HeLa cells treated with HTI-286 (2) (panel A), 6 (panel B) and 11 (panel C) at the indicated concentrations for 24 h. Cells were fixed and labeled with propidium iodide and analyzed by flow cytometry as described in the Experimental section.
Scheme 1
Scheme 1
Synthesis of aldehyde components 13–16. Reagents and conditions: (a) isobutyraldehyde, [Pd(η3-allyl)Cl]2, Q-phos, Cs2CO3, THF, reflux (13: 75%; 14: 57%; 15: 50%; 16: 46%).
Scheme 2
Scheme 2
First multicomponent approach: the 4C-Ugi reaction. Reagents and conditions: (a) MeOH, MgSO4, rt (18a: 32%; 18b: 31%; 19a: 37%; 19b: 38%).
Scheme 3
Scheme 3
Synthesis of analogues 5 and 6. Reagents and conditions: (a) LiOH, 50% aq. MeOH, rt; then (b) compound 20, HBTU, DIPEA, CH2Cl2, rt (21: overall 58%; 22: overall 52%). (c) LiOH, 50% aq. MeOH, 60 °C (5: 76%; 6: 65%).
Scheme 4
Scheme 4
Second multicomponent approach: the 3C-Ugi-like reaction. Synthesis of analogues 7–9. Reagents and conditions: (a) MeOH, MgSO4, rt (7: 51%; 8: 68%; 9: 64%).
Scheme 5
Scheme 5
Synthesis of the isocyanopeptide 23. Reagents and conditions: (a) acetic formic anhydride, CH2Cl2, 0 °C to rt (25: quant. yield). (b) N-methylmorpholine, diphosgene, THF, −30 °C to 0 °C (23: 80%).
Scheme 6
Scheme 6
Third multicomponent approach: the 3C-Ugi–Joullié reaction. Synthesis of analogues 10–12. Reagents and conditions: (a) MeOH, rt (27: 46%). (b) Iodine, aq. Na2S2O3, THF/H2O, rt (28: 85%). (c) (Boc)2O, CH2Cl2, rt (29: 92%). (d) LiOH, 50% aq. MeOH, rt; then (e) compound 20, HBTU, DIPEA, CH2Cl2, rt (10: overall 47%). (f) 50% TFA in CH2Cl2, rt (30: quant. yield). (g) Acetone, Na(OAc)3BH, AcOH, CH2Cl2, rt (11: quant. yield). (h) Cyclohexenone, Na(OAc)3BH, AcOH, CH2Cl2, rt (12: quant. yield).
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