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

Sreejith Shankar P; Monica Sani; Fiona R Saunders; Heather M Wallace; Matteo Zanda

doi:10.1055/s-0030-1260806

LETTER

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

Sreejith Shankar P^a, Monica Sani*^b,d,, Fiona R Saunders^c, Heather M Wallace^c, 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

Abstract

Alle Artikel dieser Rubrik

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

Volltext

Referenzen

References and Notes

<A NAME="RD09311ST-1">1</A> Sasse F. Steinmetz H. Höfle H. Reichembach H.
J. Antibiot. 2000, 53: 879

<A NAME="RD09311ST-2">2</A> Steinmetz H. Glaser N. Herdtweck E. Sasse F. Reichenbach H. Höfle G. Angew. Chem. Int. Ed. 2004, 43: 4888 ; Angew. Chem. 2004, 116, 4996

<A NAME="RD09311ST-3">3</A> For a recent study on the tubulin-bound structure of tubulysin A, see: Kubicek K. Grimm SK. Orts J. Sasse F. Carlomagno T. Angew. Chem. Int. Ed. 2010, 49: 4809

<A NAME="RD09311ST-4">4</A> Jackson JR. Patrick DR. Dar MM. Huang PS. Nat. Rev. Cancer 2007, 7: 107

<A NAME="RD09311ST-5">5</A> Höfle G. Glaser N. Leibold T. Karama U. Sasse F. Steinmetz H. Pure Appl.Chem. 2003, 75: 167

<A NAME="RD09311ST-6">6</A> For a review on drug-conjugated monoclonal antibodies for the treatment of cancer, see: Lambert JM. Curr. Opin. Pharmacol. 2005, 5: 543

<A NAME="RD09311ST-7A">7a</A> Leamon CP. Reddy JA. Vetzel M. Dorton R. Westrick E. Parker N. Wang Y. Vlahov I. Cancer Res. 2008, 68: 9839

<A NAME="RD09311ST-7B">7b</A> Vlahov IR. Wang Y. Kleindl PJ. Leamon CP. Bioorg. Med. Chem. Lett. 2008, 18: 4558

<A NAME="RD09311ST-7C">7c</A> Reddy JA. Dorton R. Dawson A. Vetzel M. Parker N. Nicoson JS. Westrick E. Klein PJ. Wang Y. Vlahov IR. Leamon CP. Mol. Pharm. 2009, 6: 1518

<A NAME="RD09311ST-7D">7d</A> Kularatne SA. Wang K. Santhapuram H.-KR. Low PS. Mol. Pharm. 2009, 6: 780

<A NAME="RD09311ST-8A">8a</A> Höfle G, Leibold T, and Steinmetz H. inventors; DE 10008089.

See also:

<A NAME="RD09311ST-8B">8b</A> Neri D. Fossati G. Zanda M. ChemMedChem 2006, 1: 175

<A NAME="RD09311ST-9">9</A> Sani M. Fossati G. Huguenot F. Zanda M. Angew. Chem. Int. Ed. 2007, 46: 3526

<A NAME="RD09311ST-10A">10a</A> Balasubramanian R. Raghavan B. Begaye A. Sackett DL. Fecik RA. J. Med. Chem. 2009, 52: 238

<A NAME="RD09311ST-10B">10b</A> Balasubramanian R. Raghavan B. Steele JC. Sackett DL. Fecik RA. Bioorg. Med. Chem. Lett. 2008, 18: 2996

<A NAME="RD09311ST-10C">10c</A> Raghavan B. Balasubramanian R. Steele JC. Sackett DL. Fecik RA. J. Med. Chem. 2008, 51: 1530

<A NAME="RD09311ST-10D">10d</A> Patterson AW. Peltier HM. Ellman JA. J. Org. Chem. 2008, 73: 4362

<A NAME="RD09311ST-10E">10e</A> Patterson AW. Peltier HM. Sasse H. Ellman JA. Chem. Eur. J. 2007, 13: 9534

<A NAME="RD09311ST-10F">10f</A> Wipf P. Wang Z. Org. Lett. 2007, 9: 1605

<A NAME="RD09311ST-10G">10g</A> Chandrasekhar S. Mahipal B. Kavitha M. J. Org. Chem. 2009, 74: 9531

<A NAME="RD09311ST-10H">10h</A> Pando O. Dörner S. Preusentanz R. Denkert A. Porzel A. Richter W. Wessjohann L. Org. Lett. 2009, 11: 5567

<A NAME="RD09311ST-10I">10i</A> Ullrich A. Herrmann J. Müller R. Kazmaier U. Eur. J. Org. Chem. 2009, 6367

<A NAME="RD09311ST-10J">10j</A> Peltier HM. McMahon JP. Patterson AW. Ellman JA. J. Am. Chem. Soc. 2006, 128: 16018

<A NAME="RD09311ST-10K">10k</A> Shibue T. Hirai T. Okamoto I. Morita N. Masu H. Azumaya I. Tamura O. Chem. Eur. J. 2010, 16: 11678

<A NAME="RD09311ST-10L">10l</A> Shibue T. Okamoto I. Morita N. Morita H. Hirasawa Y. Hosoya T. Tamura O. Bioorg. Med. Chem. Lett. 2011, 21: 431

<A NAME="RD09311ST-10M">10m</A> Wang Z. McPherson PA. Raccor BS. Balachandran R. Zhu G. Day BW. Vogt A. Wipf P. Chem. Biol. Drug Des. 2007, 70: 75

<A NAME="RD09311ST-11">11</A> Wipf P. Takada T. Rishel MJ. Org. Lett. 2004, 6: 4057

<A NAME="RD09311ST-12">12</A> Cheng ZZ. Hamada Y. Shioiri T. Synlett 1997, 109

<A NAME="RD09311ST-13">13</A> Phillips AJ. Uto Y. Wipf P. Reno MJ. Williams DR. Org. Lett. 2000, 2: 1165

<A NAME="RD09311ST-14">14</A> Barrish JC. Singh J. Spergel SH. Han W.-C. Kissick TP. Kronenthal DR. Mueller RH. J. Org. Chem. 1993, 58: 4494

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]⁺.

For other methods accomplishing the mentioned transfor-mation, see:

<A NAME="RD09311ST-16A">16a</A> Williams DR. Lowder PD. Gu Y.-G. Brooks DA. Tetrahedron Lett. 1997, 38: 331

<A NAME="RD09311ST-16B">16b</A> Chattopadhyay SK. Kempson J. McNeil A. Pattenden G. Reader M. Rippon DE. Waite D. J. Chem. Soc., Perkin Trans. 1 2000, 2415

<A NAME="RD09311ST-17">17</A> Phillips AJ. Uto Y. Wipf P. Reno MJ. Williams DR. Org. Lett. 2000, 2: 1165

<A NAME="RD09311ST-18">18</A> Corey EJ. Helal CJ. Angew. Chem. Int. Ed. 1998, 37: 1986 ; Angew. Chem. 1998, 110, 2092

Characterisation Data for Compound 5b
R _f = 0.43 (EtOAc-hexane = 45:55). FT-IR (film): ν_max = 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]⁺.

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]⁺.

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]⁺.

<A NAME="RD09311ST-22">22</A> Fraser AV. Woster PM. Wallace HM. Biochem. J. 2002, 367: 307 ; and references cited therein