Synlett 2016; 27(07): 977-983
DOI: 10.1055/s-0035-1561314
synpacts
© Georg Thieme Verlag Stuttgart · New York

The Preorganization of Atropisomers to Increase Target Selectivity

Christopher J. Nalbandiana, David E. Hechtb, Jeffrey L. Gustafson*a
  • aDepartment of Chemistry and Biochemistry, San Diego State University, 5500 Campanile Dr., San Diego, CA, 92182-1030, USA   Email: JGustafson@mail.sdsu.edu
  • bSchool of Mathematics, Science & Engineering, Southwestern College, 900 Otay Lakes Rd., Chula Vista CA, 91910, USA
Further Information

Publication History

Received: 16 November 2015

Accepted after revision: 09 December 2015

Publication Date:
20 January 2016 (eFirst)

Abstract

Atropisomerism is a form of chirality that arises from differential substitution around a bond that renders the rotational isomers enantiomers. Depending on the degree of hindrance to bond rotation, atropisomers can exist as either stable isolable enantiomers or rapidly racemizing atropisomeric mixtures. Many biologically active small molecules exist as rapidly interconverting atropisomers, however, only one of the possible atropisomers possesses the desired activity. The presence of the nonrelevant atropisomer via spontaneous racemization can result in off-target activities that can lead to side effects. We have hypothesized that preorganizing (locking) a freely interconverting atropisomeric axis in a promiscuous scaffold into the target relevant atropisomer can serve as a general strategy towards more selective small molecule inhibitors. This article outlines recent literature on atropisomerism in drug discovery as well as our recent efforts towards increasing the target selectivity of small molecule kinase inhibitors through ‘atropisomer preorganization’.

 
  • References

  • 1 LaPlante SR. D, Fader L, Fandrick KR, Fandrick DR, Hucke O, Kemper R, Miller SP. F, Edwards PJ. J. Med. Chem. 2011; 54: 7005
  • 2 Dodou K, Anderson RJ, Lough WJ, Small DA. P, Shelley MD, Groundwater PW. Bioorg. Med. Chem. 2005; 13: 4228
  • 3 LaPlante SR, Edwards PJ, Fader LD, Jakalian A, Hucke O. ChemMedChem 2011; 6: 505
  • 4 Zask A, Murphy J, Ellestad GA. Chirality 2013; 25: 265
  • 5 Clayden J, Moran WJ, Edwards PJ, LaPlante SR. Angew. Chem. Int. Ed. 2009; 48: 6398
  • 6 Porter J, Payne A, Whitcombe I, de Candole B, Ford D, Garlish R, Hold A, Hutchinson B, Trevitt G, Turner J, Edwards C, Watkins C, Davis J, Stubberfield C. Bioorg. Med. Chem. Lett. 2009; 19: 1767
  • 7 Takahashi H, Wakamatsu S, Tabata H, Oshitari T, Harada A, Inoue K, Natsugari H. Org. Lett. 2011; 13: 760
  • 8 Xing L, Devadas B, Devraj RV, Selness SR, Shieh H, Walker JK, Mao M, Messing D, Samas B, Yang JZ, Anderson GD, Webb EG, Monahan JB. ChemMedChem 2012; 7: 273
  • 9 Yoshida K, Itoyama R, Yamahira M, Tanaka J, Lozach O, Durieu E, Fukuda T, Ishibashi F, Meijer L, Iwao M. J. Med. Chem. 2013; 56: 7289
  • 10 LaPlante SR, Forgione P, Boucher C, Coulombe R, Gillard J, Hucke O, Jakalian A, Joly M.-A, Kukolj G, Lemke C, McCollum R, Titolo S, Beaulieu PL, Stammers T. J. Med. Chem. 2014; 57: 1944
  • 11 Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. Science 2002; 298: 1912
  • 12 Cohen P, Alessi DR. ACS Chem. Biol. 2012; 8: 96
  • 13 Cohen P. Nat. Rev. Drug Discov. 2002; 1: 309
  • 14 Smith CC, Shah NP. Hematology 2011; 2011: 121
  • 15 Cui JJ, Tran-Dubé M, Shen H, Nambu M, Kung P.-P, Pairish M, Jia L, Meng J, Funk L, Botrous I, McTigue M, Grodsky N, Ryan K, Padrique E, Alton G, Timofeevski S, Yamazaki S, Li Q, Zou H, Christensen J, Mroczkowski B, Bender S, Kania RS, Edwards MP. J. Med. Chem. 2011; 54: 6342
  • 16 Mulligan LM. Nat. Rev. Cancer 2014; 14: 173
  • 17 Wells SA, Gosnell JE, Gagel RF, Moley J, Pfister D, Sosa JA, Skinner M, Krebs A, Vasselli J, Schlumberger M. J. Clin. Oncol. 2010; 28: 767
  • 18 Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R, Pfister DG, Cohen EE. W, Janisch L, Nauling F, Hong DS, Ng CS, Ye L, Gagel RF, Frye J, Müller T, Ratain MJ, Salgia R. J. Clin. Oncol. 2011; 29: 2660
  • 19 Fabian MA, Biggs WH, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lelias J.-M, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ. Nat. Biotechnol. 2005; 23: 329
  • 20 Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. Nat. Biotechnol. 2011; 29: 1046
  • 21 Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. Nat. Biotechnol. 2011; 29: 1039
  • 22 Cornelison M, Jabbour EJ, Welch MA. J. Support. Oncol. 2012; 10: 14
  • 23 Laufer S, Bajorath J. J. Med. Chem. 2014; 57: 2167
  • 24 Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ, McLauchlan H, Klevernic I, Arthur JS. C, Alessi DR, Cohen P. Biochem. J. 2007; 408: 297
  • 25 Smyth LA, Collins I. J. Chem. Biol. 2009; 2: 131
  • 26 Goldstein DM, Gray NS, Zarrinkar PP. Nat. Rev. Drug Discov. 2008; 7: 391
  • 27 Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. Nat. Biotechnol. 2011; 29: 1046
  • 28 Breitenlechner CB, Kairies NA, Honold K, Scheiblich S, Koll H, Greiter E, Koch S, Schäfer W, Huber R, Engh RA. J. Mol. Biol. 2005; 353: 222
  • 29 Henderson JL, Kormos BL, Hayward MM, Co KJ, Jasti J, Kurumbail RG, Wager TT, Verhoest PR, Noell GS, Chen Y, Needle E, Berger Z, Steyn SJ, Houle C, Hirst WD, Galatsis P. J. Med. Chem. 2015; 58: 419
  • 30 Maddox SM, Nalbandian CJ, Smith DE, Gustafson JL. Org. Lett. 2015; 17: 1042
  • 31 Smith DE, Marquez I, Lokensgard ME, Rheingold AL, Hecht DA, Gustafson JL. Angew. Chem. Int. Ed. 2015; 54: 11754
  • 32 Zhang J, Yang PL, Gray NS. Nat. Rev. Cancer 2009; 9: 28
  • 33 Liu Q, Sabnis Y, Zhao Z, Zhang T, Buhrlage SJ, Jones LH, Gray NS. Chem. Biol. 2013; 20: 146
  • 34 Alao JP, Sunnerhagen P. J. Med. Chem. 2012; 55: 4872