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Synlett 2011(12): 1673-1676  
DOI: 10.1055/s-0030-1260806
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Total Synthesis and Cytotoxicity Evaluation of an Oxazole Analogue of Tubulysin U

Sreejith Shankar Pa, Monica Sani*b,d,, Fiona R Saundersc, Heather M Wallacec, Matteo Zanda*b,c
a Dipartimento di Chimica, Materiali e Ingegneria Chimica ‘Giulio Natta’, Politecnico di Milano, Via Mancinelli 7, 20131 Milan, Italy
b C. N. R - Istituto di Chimica del Riconoscimento Molecolare, Sezione ‘A. Quilico’, Via Mancinelli 7, 20131 Milano, Italy
c Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK Website: http://www.abdn.ac.uk/kosterlitz/
e-Mail: m.zanda@abdn.ac.uk;
d KemoTech, KemoTech s.r.l., Parco Scientifico della Sardegna, Edificio 3, Loc. Piscinamanna, 09010 Pula (CA), Italy
Further Information

Publication History

Received 25 March 2011
Publication Date:
21 June 2011 (online)

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Abstract

Tubulysins are strongly cytotoxic natural tetrapeptides with potent antiproliferative, antimitotic, and antiangiogenic activities which might find use in oncology. We herein report the first total synthesis of a stereoisomerically pure oxazole analogue of tubulysin U, which was found to be more cytotoxic than the thiazole-containing natural product. Additionally, we have developed an improved and scalable synthetic route towards the Tup fragment of the tubulysins.

Key words

tubulysin - oxazole - SAR study - chemotherapy - cytotoxicity

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Characterisation Data for Compound 4b
R f  = 0.35 (EtOAc-hexane = 3:7). ¹H NMR (400 MHz, CDCl3): δ = 8.21 (s, 1 H), 4.22 (q, J = 7.1 Hz, 2 H), 2.51 (s, 3 H), 1.19 (t, J = 7.1 Hz, 3 H). ¹³C NMR (100.5 MHz, CDCl3): δ = 185.1, 160.1, 157.6, 146.0, 134.7, 61.5, 26.6, 14.1. ESI-LCMS: m/z = 183.9 [M + H]+, 205.8 [M + Na]+.

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Characterisation Data for Compound 5b
R f  = 0.43 (EtOAc-hexane = 45:55). FT-IR (film): νmax = 3374.8, 1734.5, 1660.4, 1505.4, 1391.9, 757.4 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 8.14 (s, 1 H), 4.84 (d, J = 10.8 Hz, 1 H), 4.72 (br s, 1 H), 4.55 (d, J = 9.3 Hz, 1 H), 4.31 (q, J = 7.1 Hz, 2 H), 3.73-3.63 (m, 1 H), 2.02 (ddd, J = 13.7, 11.3, 2.5 Hz, 1 H), 1.80-1.65 (m, 2 H), 1.38 (s, 9 H), 1.30 (t, J = 7.1 Hz, 3 H), 0.90 (d, J = 6.9 Hz, 3 H), 0.88 (d, J = 6.9 Hz, 3 H). ¹³C NMR (100.5 MHz, CDCl3): δ = 165.6, 161.1, 157.6, 143.9, 133.2, 80.1, 64.6, 61.0, 52.1, 39.1, 32.1, 28.2, 19.2, 18.2, 14.2. ESI-LCMS: m/z = 379.1 [M + Na]+.

20

Characterisation Data for Compound 21
R f  = 0.3 (MeOH-CH2Cl2 = 1:9). [α]D ²³ +8.6 (c 1.0, MeOH). ¹H NMR (400 MHz, CD3OD): δ = 7.46-7.15 (m, 5 H), 3.63 (s, 3 H), 3.59-3.47 (m, 1 H), 3.04 (dd, J = 19.9, 6.2 Hz, 1 H), 2.91 (dd, J = 13.7, 7.7 Hz, 1 H), 2.79-2.65 (m, 1 H), 2.08-1.95 (m, 1 H), 1.16 (d, J = 6.9 Hz, 3 H). ¹³C NMR (100.5 MHz, CD3OD): δ = 178.1, 137.8, 131.3, 130.9, 129.3, 53.3, 41.1, 37.9, 37.7, 18.7. ESI-LCMS: m/z = 221.9 [M + H]+.

21

Characterisation Data for the Tubulysin U Analogue oxa-1
R f  = 0.53 (MeOH-CHCl3 = 12:88). ¹H NMR (250 MHz, CD3OD): δ = 8.14 (s, 1 H), 7.19-7.00 (m, 5 H), 5.61 (dd, J = 11.1, 2.4 Hz, 1 H), 4.24-4.22 (m, 1 H), 4.10 (d, J = 8.3 Hz, 1 H), 3.90-3.75 (m, 1 H), 3.13-2.88 (m, 2 H), 2.77 (d, J = 6.6 Hz, 2 H), 2.52-2.36 (m, 2 H), 2.35 (s, 3 H), 2.27-2.09 (m, 1 H), 2.02 (s, 3 H), 1.99-1.10 (m, 13 H), 1.05 (d, J = 6.8 Hz, 3 H), 0.92-0.74 (m, 12 H). ¹³C NMR (63 MHz, CD3OD): δ = 176.7, 173.7, 173.1, 171.6, 163.4, 162.1, 143.0, 139.7, 137.5, 130.5, 129.3, 127.3, 69.5, 66.9, 59.6, 56.3, 51.8, 50.7, 44.0, 42.0, 39.3, 37.5, 35.7, 33.8, 32.7, 31.0, 25.9, 25.3, 23.5, 20.6, 19.5, 18.6, 16.2, 14.4, 11.1. ESI-LCMS: m/z = 698.2 [M + H]+, 720.2 [M + Na]+.