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. 2011 Feb 14;2(2):154-159.
doi: 10.1021/ml100230n.

Synthesis and Structure-Activity Relationships of Benzothienothiazepinone Inhibitors of Protein Kinase D

Karla Bravo-Altamirano  1 , Kara M George, Marie-Céline Frantz, Courtney R Lavalle, Manuj Tandon, Stephanie Leimgruber, Elizabeth R Sharlow, John S Lazo, Q Jane Wang, Peter Wipf
Affiliations

Synthesis and Structure-Activity Relationships of Benzothienothiazepinone Inhibitors of Protein Kinase D

Karla Bravo-Altamirano et al. ACS Med Chem Lett. .

Abstract

Protein kinase D (PKD) is a member of a novel family of serine/threonine kinases that regulate fundamental cellular processes. PKD is implicated in the pathogenesis of several diseases, including cancer. Progress in understanding the biological functions and therapeutic potential of PKD has been hampered by the lack of specific inhibitors. The benzoxoloazepinolone CID755673 was recently identified as the first potent and selective PKD inhibitor. The study of structure-activity relationships (SAR) of this lead structure led to further improvements in PKD1 potency. We describe herein the synthesis and biological evaluation of novel benzothienothiazepinone analogs. We achieved a ten-fold increase in the in vitro PKD1 inhibitory potency for the second generation lead kb-NB142-70 and accomplished a transition to an almost equally potent novel pyrimidine scaffold, while maintaining excellent target selectivity. These promising results will guide the design of pharmacological tools to dissect PKD function and pave the way for the development of potential anti-cancer agents.

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Figures

Scheme 1
Scheme 1. Synthesis of the β-Carboline Analogue kb-NB123-57
Reagents and conditions: (a) H2SO4, EtOH, reflux, 5 h. (b) Pd/C, NH4HCO3, MeOH, reflux, 2 h.
Scheme 2
Scheme 2. Synthesis of the Benzothienothiazepinone Analogues kb-NB142-70 and kb-NB165-09
Reagents and conditions: (a) BnBr, NaOH, EtOH, rt, 14 h. (b) (i) SOCl2, pyr, DMF, PhCl, 120 °C, 22 h; (ii) Et3N, MeOH, reflux, 12 h. (c) DBU, DMF, rt, 1.5 h; then 70 °C, 12 h. (d) BBr3, DCM, −20 to 0 °C, 2.5 h. (e) MeI, K2CO3, DMF, rt, 12 h.
Scheme 3
Scheme 3. Synthesis of the Benzothienothiazocinones kb-NB165-92 and kb-NB184-02
Reagents and conditions: (a) (i) ClSO3H, CCl4, rt, overnight; (ii) CS2, NaOH, EtOH/H2O, 0 °C to reflux, 40 min. (b) conc HCl, reflux, N2, 14 days. (c) 5, DBU, DMF, rt, 2 h; then 70 °C, 18 h. (d) BBr3, DCM, −20 °C to rt, 2 h. (e) MeI, K2CO3, DMF, rt, overnight.
Scheme 4
Scheme 4. Synthesis of the Azidobenzothienothiazepinone Analogue mcf292-08
Reagents and conditions: (a) Et3N, MeOH, 40−50 °C, 4 h. (b) Tf2O, Et3N, DMAP, DCM, rt, 2 h. (c) DBU, DMF, rt, 1.5 h; then 70 °C, 13 h. (d) SnCl2, EtOH, reflux, 5 h. (e) t-BuONO, TMSN3, MeCN, rt, 1.5 h.
Scheme 5
Scheme 5. Synthesis of the Thiazepinothiophenopyrimidinone Analogue kmg-NB4-23
Reagents and conditions: (a) (i) KOCN, AcOH, H2O, rt, 20 h; (ii) 2 N NaOH, rt, 2 h. (b) POCl3, MeCN, reflux, 2 days. (c) H2, Pd/C, EtOH, Na2CO3, rt, 24 h. (d) NaOMe, MeOH, reflux, 6 h. (e) AcOH, Br2, 70 °C, 24 h. (f) (i) TMPMgCl·LiCl, −50 °C, 2 h; (ii) MeCO2CN. (g) DBU, DMF, rt, 1.5 h; then 70 °C, 10 h.
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