Microwave-Assisted Synthesis
of KN-93, a Potent and Selective Inhibitor of Ca²+/Calmoduline-Dependent
Protein Kinase II

Claudio Bruno; Giovanni Lentini; Alessia Catalano; Alessia Carocci; Angelo Lovece; Antonia Di Mola; Maria Maddalena Cavalluzzi; Paolo Tortorella; Fulvio Loiodice; Guido Iaccarino; Pietro Campiglia; Ettore Novellino; Carlo Franchini

doi:10.1055/s-0030-1258298

PAPER

Microwave-Assisted Synthesis of KN-93, a Potent and Selective Inhibitor of Ca^²+/Calmoduline-Dependent Protein Kinase II

Claudio Bruno^a, Giovanni Lentini^a, Alessia Catalano^a, Alessia Carocci^a, Angelo Lovece^a, Antonia Di Mola^a, Maria Maddalena Cavalluzzi^a, Paolo Tortorella^a, Fulvio Loiodice^a, Guido Iaccarino^b, Pietro Campiglia^c, Ettore Novellino^d, Carlo Franchini*^a
^a Dipartimento Farmaco-Chimico, Università di Bari, Via E. Orabona 4, 70126 Bari, Italy
Fax: +39(080)5442724; e-Mail: cfranc@farmchim.uniba.it;
^b Dipartimento di Medicina Clinica e Scienze Cardiovascolari e Immunologiche, Università degli Studi di Napoli Federico II, Corso Umberto I, 80138 Napoli, Italy
^c Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy
^d Dipartimento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy

Abstract

All articles of this category

Abstract

Convenient synthetic routes to KN-93, N-(2-{[[(2E)-3-(4-chlorophenyl)prop-2-enyl](methyl)amino]methyl}phenyl)-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide, a well-known Ca^²+/calmoduline-dependent protein kinase II (CaMKII) inhibitor, are described. The methods proposed start from easily available reagents and allow ready preparation of the final compound in moderate overall yields. Most of the synthetic steps proposed were microwave assisted.

Key words

Heck reaction - sulfonamides - enzymes - multicomponent reaction - medicinal chemistry

Full Text

References

<A NAME="RT14310SS-1">1</A> Soderling TR. Trends Biochem. Sci. 1999, 24: 232

<A NAME="RT14310SS-2">2</A> Hook SS. Means AR. Annu. Rev. Pharmacol. Toxicol. 2001, 41: 471

<A NAME="RT14310SS-3">3</A> Soderling TR. Stull JT. Chem. Rev. 2001, 101: 2341

<A NAME="RT14310SS-4">4</A> Hudmon A. Schulman H. Biochem. J. 2002, 364: 593

<A NAME="RT14310SS-5">5</A> Hudmon A. Schulman H. Annu. Rev. Biochem. 2002, 71: 473

<A NAME="RT14310SS-6">6</A> Griffith LC. Cell 2008, 133: 397

<A NAME="RT14310SS-7">7</A> Hanson PI. Schulman H. Annu. Rev. Biochem. 1992, 61: 559

<A NAME="RT14310SS-8">8</A> Braun AP. Schulman H. Annu. Rev. Physiol. 1995, 57: 417

<A NAME="RT14310SS-9">9</A> Soderling TR. Adv. Second Messenger Phosphoprotein Res. 1995, 30: 17

<A NAME="RT14310SS-10">10</A> Schulman H. Braun A. In Calcium as a Cellular Regulator Crafoli E. Klee C. Oxford University Press; New York: 1999. p.311-343

<A NAME="RT14310SS-11">11</A> Heist EK. Schulman H. Cell Calcium 1998, 23: 103

<A NAME="RT14310SS-12">12</A> Soderling TR. Chang B. Brickey D. J. Biol. Chem. 2001, 276: 3719

<A NAME="RT14310SS-13">13</A> Wang ZJ. Tang L. Xin L. Eur. J. Pharmacol. 2003, 465: 199

<A NAME="RT14310SS-14">14</A> Luo F. Yang C. Chen Y. Shukla P. Tang L. Wang LX. Wang ZJ. J. Pharmacol. Exp. Ther. 2008, 325: 267

<A NAME="RT14310SS-15">15</A> McKinsey TA. Cardiovasc. Res. 2007, 73: 667

<A NAME="RT14310SS-16">16</A> Cai H. Liu D. Garcia JGN. Cardiovasc. Res. 2008, 77: 30

<A NAME="RT14310SS-17">17</A> Sumi M. Kiuchi K. Ishikawa T. Ishii A. Hagiwara M. Nagatsu T. Hidaka H. Biochem. Biophys. Res. Commun. 1991, 181: 968

<A NAME="RT14310SS-18">18</A> Hidaka H, Ishikawa T, Inoe T, Morita T, Nakano H, Yuasa M, Naito K, Sakuma O, Kidokoro S, and Tachikawa M. inventors; Jpn. Kokai Tokkyo Koho JP 06293730. ; Chem. Abstr. 1995, 122, 314463

<A NAME="RT14310SS-19">19</A> Bruno C. Carocci A. Catalano A. Cavalluzzi MM. Corbo F. Franchini C. Lentini G. Tortorella V. Chirality 2006, 18: 227

<A NAME="RT14310SS-20">20</A> Boyer JH. Alul H. J. Am. Chem. Soc. 1959, 81: 2136

<A NAME="RT14310SS-21">21</A> Hendrickson JB. Bergeron R. Tetrahedron Lett. 1970, 345

<A NAME="RT14310SS-22">22</A> Bogdal D. In Microwave-Assisted Organic Synthesis Vol. 25: Bäckvall J.-E. Baldwin JE. Williams RM. Elsevier; Oxford: 2005. p.55-56

<A NAME="RT14310SS-23">23</A> Battistuzzi G. Cacchi S. Fabrizi G. Org. Lett. 2003, 5: 777

<A NAME="RT14310SS-24">24</A> Mancuso AJ. Huang S.-L. Swern D. J. Org. Chem. 1978, 43: 2480

<A NAME="RT14310SS-25">25</A> Penjiševic J. Šukalovic V. Andrić D. Kostić-Rajačić S. Šoškic V. Roglić G. Arch. Pharm. Chem. Life Sci. 2007, 340: 456

<A NAME="RT14310SS-26">26</A> Daubresse N. Francesch C. Rolando C. Tetrahedron 1998, 54: 10761

<A NAME="RT14310SS-27">27</A> Still WC. Kahn M. Mitra A. J. Org. Chem. 1978, 43: 2923

<A NAME="RT14310SS-28">28</A> Olsen DK. Torian BE. Morgan CD. Braun LL.
J. Org. Chem. 1980, 45: 4049

Microwave-Assisted Synthesis of KN-93, a Potent and Selective Inhibitor of Ca²+/Calmoduline-Dependent Protein Kinase II

Microwave-Assisted Synthesis of KN-93, a Potent and Selective Inhibitor of Ca^²+/Calmoduline-Dependent Protein Kinase II