CAPITULO II: ESTRATEGIA DIGITAL APRENDO EN CASA
2.4 Ventajas y desventajas
Understanding molecular recognition is important in the construction of new molecules. This can result in gaining control of intermolecular interactions, thereby providing opportunities to fine-tune specific properties (thermal stability, solubility, hygroscopicity, etc) of a variety of compounds.
Therefore, this dissertation will focus on:
I. Understanding molecular recognition through systematic studies of acetamidopyridine
Acetamidopyridine were of interest because pyridine derivatives exhibit high biological activity as is demonstrated in wide variety of pharmaceutical compounds.52 Moreover the acetamide derivatives have shown to be effective inducers of cell growth.53 Furthermore, by understanding the molecular recognition processes of this small molecule will provide us with valuable information, which can be used to understand larger and more complicated molecules. Therefore a series of acetamidopyridine derivatives will be designed and synthesized. Subsequent co-crystallizations with hydrogen-bond donors, will allow for a systematic study of molecular recognition preferences. Additionally, these supramolecular reagents will also be employed for organizing coordination complexes into extended architectures, using robust self-complementary hydrogen-bonding capability.
II. Balancing intermolecular hydrogen and halogen bonding
Halogen bonding has been shown to have similar strength and directionality as the hydrogen bond. To probe the strength of the halogen bond a collection of supramolecular reagents having the capability to participate in both hydrogen and halogen bonding will be tested. Additionally, Etter’s rule which states that the best hydrogen-bond donor will interact with the best hydrogen-bond acceptor, will be tested using MEPs in ranking the strength of the hydrogen and halogen bond, thus allowing for better predictability.
III. Establishing the interaction of preference of the XB with thienyl compounds A series of supramolecular reagents containing sulfur atoms will be synthesized.
Subsequent co-crystallization reactions will be carried on these supramolecular reagents using a variety of halogen bond donors, in order to determine whether XB in these series is strictly electrostatic or a hard/soft acid and base interaction.
IV. Applying molecular recognition in fine-tuning physicochemical properties Finally, systematic studies will be carried out on a series of API’s with the ultimate goals of fine-tuning the melting behavior and aqueous solubility.
References
1 (a) Lehn, J.-M. Supramolecular Chemistry. Weinheim: Wiley-VCH, 1995; (b) Gellman, S.H. Chem. Rev., 1997, 97, 1231.
2 (a) MacGillivray, L. CrystEngComm., 2004, 6, 77; (b) Lehn, J.–M. Science, 2002, 295, 2400; (c) Etter, M. C. J. Phys. Chem., 1991, 95, 4601; (d) Moulton, B.; Zaworotko, M.J. Chem. Rev., 2001, 101, 1629;
(e) Pauling, L. The Nature of the Chemical Bond, Cornell University Press: Ithaca, NY, 1939; (f) Lehn, J.–M. Angew. Chem.Int. Ed. Engl., 1990, 29, 1304; (g) Steed J. W.; Atwood, J. L. Supramolecular Chemistry, John Wiley and Sons Ltd, Chichester, 2000.
3 Fischer, E. Ber. Deutsch. Chem. Ges. 1894, 3, 267.
4 (a) Bernstein, J. J. Phys D: Appl. Phys., 1993, 26, B66; (b) Bernstein, J. Organic Solid State Chemistry, Desiraju G.R. Ed. Elsevier: New York, 1987, 32, 471.
5 (a) Reference 2b; (b) Hosseini, M.-W. Chem. Commun. 2005, 5825.
6 (a) Aakeröy, C. B. Acta Crystallogr., Sect. B: Struct. Sci., 1997, 53, 569; (b) Desiraju, G. R. Acc. Chem.
Res., 2002, 35, 565; (c) Hosseini, M. W. CrystEngComm, 2004, 6, 318; (d) Brammer, L. Chem. Soc. Rev., 2004, 33, 476; (e) Aakeröy C. B.; Beatty, A. M. Aust. J. Chem., 2001, 54, 409; (f) Caulder D. L.;
Raymond, K. N. Acc. Chem. Res., 1999, 32, 975; (g) Reinhoudt D. N.; Crego-Calama, M. Science, 2002, 295, 2403; (h) Braga, D.; Desiraju, G. R; Miller, J. S.; Orpen A. G.; Price, S. L. CrystEngComm, 2002, 4, 500; (i) Braga, D.; Maini, L.; Polito M.; Grepioni, F. Struct. Bond., 2004, 111, 1; (j) Lewis G.; Orpen, A.
G. Chem. Commun., 1998, 1873; (k) Prins, L. J.; Reinhoudt D. N.; Timmerman, P. Angew. Chem. Int. Ed., 2001, 40, 2382; (l) Zimmerman, S. C. and Corbin, P. S. Struct. Bond., 2000, 96, 63.
7 (a) Aakeröy, C. B.; Desper, J.; Helfrich, B. A. CrystEngComm, 2004, 6, 19–24; (b) Aakeröy, C. B.;
Desper, J.; Scott, B. M. T. Chem. Commun., 2006, 1445; (c) Aakeröy, C. B.; Schultheiss, N.; Desper, J.;
Moore, C. New J. Chem., 2006, 30, 1452; (d) Aakeröy, C. B.; Fasulo, M. E.; Desper, J. CrystEngComm, 2006, 8, 586; (e) Steed, J.W.; Turner, D.R.; Wallace, K.J. Core Concepts in Supramolecular Chemistry and Nanochemistry, John Wiley & Sons, Ltd, 2007.
8 (a) Moulton B.; Zaworotko, M. J Chem. Rev., 2001, 101, 1629; (b) Desiraju, G. R. Acc. Chem. Res., 2002, 35, 565; (c) Hosseini, M. W. CrystEngComm, 2004, 6, 318; (d) MacGillivray, L. R. CrystEngComm, 2004, 6, 77; D. Braga, Chem. Commun., 2003, 2751; (e) Brammer, L. Chem. Soc. Rev., 2004, 33, 476.
9 Lehn, J.-M. Angew. Chem. Int. Ed. Engl. 1990, 29, 1304.
10 Watson, J.D.; Crick, F.H.C. Nature (Landon) 1953, 171, 737.
11 (a) Aakeröy, C.B.; Hussain, I.; Forbes, S.; Desper, J. Aust. J. Chem. 2009, 62, 899; (b) Fujita, M.; Kwon, Y.-J.; Washizu, S.; Ogura, K. J. Am. Chem. Soc. 1994, 116, 1151; (c) Yaghi, O.M.; Li, H. J. Am. Chem.
Soc. 1996, 118, 295; (d) Aakeröy, C.B.; Beatty, A.M. Leinen, D.S. J. Am. Chem. Soc. 1998, 120, 7383.
12 (a) Reference 2f; (b) Whitesides, G.M.; Simanek, E.E.; Mathias, J.P.; Seto, C.T.; Chin, D.N.; Mammen, M.; Gordon, D.M. Acc. Chem. Res. 1995, 28, 37.
13 Desiraju, G.R. Angew. Chem. Int. Ed. Engl. 1995, 34, 2311.
14 (a) Nangia, A.; Desiraju, G.R. Topics in Current Chemistry “Supramolecular Synthons and Pattern Recognition” 1998, 198/1998, 57; (b) Aakeröy, C.B. Acta Cryst. 1997, B53, 569.
15 (a) Etter, M.C. Acc. Chem. Rev. 1990, 23, 120; (b) Taylor, R.; Kennard, O. Acc. Chem. Res. 1984, 17,
20 Burrows, A.D. Struct. Bond 2004, 108, 55.
21 Reference 14a
22 Aakeröy, C.B.; Seddon, K.R. Chem. Soc. Rev. 1993, 22, 397.
23 Steed, J.W.; Atwood, J.L. Supramolecular Chemistry, 2nd Ed. John Wiley & Sons, Ltd. 2009.
24 (a) Reference 12a; (b) Reference 11
25 Walsh, R.D.B.; Bradner, M.W.; Fleischman, S.; Morales, L.A.; Moulton, B.; Rodriguez-Hornedo, N.;
Zaworotko, M.J. Chem. Commun. 2003, 186.
26 (a) Bis, J.; Zaworotko, M.J. Cryst. Growth Des. 2005, 5, 1169; (b) Steiner, T. Acta Crystallogr. Sect. B:
Struct. Sci. 2001, 57, 103; (c) Vishweshwar, P.; Nangia, A.; Lynch, V.M. Cryst. Growth Des. 2003, 3, 783;
(d) Etter, M.C.; Adsmond, D.A. J. Chem. Soc. Chem. Commun. 1990, 8, 589; (e) Aakeröy, C.B.; Beatty, A.M.; Helfrich. A. Cryst. Growth Des. 2002, 2, 325; (f) Vangala, V.R.; Mondal, R.; Broder, C.K.; Howard, J.A.K.; Desiraju, G.R. Cryst. Growth Des. 2005, 5, 99; (g) Videnova-Adrabinska, V.; Etter, M.C. J. Chem.
Crystallogr. 1995, 25, 823.
27 Aakeröy, C.B.; Salmon, D.J. CrystEngComm. 2005, 7, 439.
28 (a) Stahly, G.P. Cryst. Growth Des. 2007, 7, 1007; (b) Vishweshwar, P.; McMahon, J.A.; Bis, J.A.;
Zaworotko, M.J. J. Pharm. Sci. 2006, 95, 499.
29 Aakeröy, C.B.; Forbes, S.; Desper, J. J. Am. Chem. Soc. 2009, 131, 17048.
30 Hunter, C.A. Angew. Chem. Int. Ed. 2004, 43, 5310.
31 Pauling, L. Proc. Natl. Acad. Sci. USA 1928, 14, 349.
32 (a) Hagelin, H.; Murray, J.S.; Brinck, T.; Berhelot, M.; Politzer, P. Can. J. Chem. 1995, 73, 483; (b) Dearden, J.C.; Ghafourian, T. J. Chem. Inf. Comput. Sci. 1999, 39, 321; (c) Platts, J.A. Phys. Chem. Chem.
Phys. 2000, 2, 973; (d) Platts, J.A. Phys. Chem. Chem. Phys. 2000, 2, 3115; (e) Zissimos, A.M.; Abraham, M.H.; Klamt, A.; Eckert, F.; Wood, J. J. Chem. Inf. Comput. Sci. 2002, 42, 1320.
33 (a) Metrangolo, P.; Neukirch, H.; Pilati, T.; Resnati, G. Acc. Chem. Res. 2005, 38, 386; (b) Metrangolo, P.; Resnati, G. Chem. Eur. J. 2001, 7, 2511.
34 (a) Metrangolo, P.; Resnati, G.; Pilati, T.; Biella, S. Struct. Bond, 2008, 126, 105; (b) Metrangolo, P.;
Pilati, T.; Resnati, G. CrystEngComm. 2006, 8, 946; (c) Pennington, W.T.; Hanks, T.W.; Arman, H.D.
Struct. Bond 2008, 126, 65.
35 Cabot, R.; Hunter, C.A. Chem. Commun. 2009, 2005.
36 (a) Desiraju, G.R. Crystal Engineering-The Design of Organic Solids, Elsevier, Amsterdam, 1989;
Desiraju, G.R. Angew. Chem. Int. Ed. Engl. 1995, 34, 2311; (c) Moulton, B.; Zaworotko, M.J. Chem. Rev.
2001, 101, 1629.
37 Almarsson, Ö.; Zaworotko, M.J. Chem. Commun. 2004, 1889.
38 Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950.
39 (a) Kerns, E.H.; Di, L. Drug-Like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization; Elsevier, Amsterdam, 2008, pp 7-9; (b) Basavoju, S.; Boström, D.; Velaga, S.P.
Pharm. Res. 2008, 25, 530.
40 Lipper, R.B. Mod. Drug Discovery 1999, 2, 55.
41 (a) Pharmaceutical Industry Profile 2006 & 2007; PhRMA: Washington, DC, 2006 & 2007; (b) Mass Spectrometry in Drug Metabolism and Pharmacokinetics; Ramanathan, R., Ed.; Wiley: Hoboken, NJ, 2009, pp 1-4.
42 Almarsson, Ö.; Gardner, C.R. Current Drug Discovery 2003, 21.
43 Stanton, M.K.; Bak, A. Cryst. Growth Des. 2008, 8, 3856.
44 Takagi, T.; Ramachandran, C.; Bermejo, M.; Yamashita, S.; Yu, L.X.; Amidon, G.L. Mol.
Pharmaceutics 2006, 3, 631.
45 Hiten, J.S.; Gunta, S.; Dasharath, M.P.; Chhagan, N.P. Biopharm. Drug Dispos. 2009, 30, 524.
46 Stegemann, S.; Leveiller, F.; Franchi, D.; de Jong, H.; Lindén, H. Eur. J. Pharm. Sci. 2007, 31, 249.
47 Takagi, T.; Ramachandran, C.; Bermejo, M.; Yamashita, S.; Yu, L.X.; Amidon, G.L. Molecular Pharmaceutics 2006, 3, 631.
48 McNamara, D.P.; Childs, S.L.; Giordano, J.; Iarricco, A.; Cassidy, J.; Manjunath, S.-S.; Mannion, R.;
O’Donnell, E.; Park, A. Pharm. Res. 2006, 23, 1888.
49 (a) Shan, N.; Zaworotko, M.J. Drug Disc. Today 2008, 8, 3856; (b) Reutzel-Edens, S.M.; Bush, J.K.;
Magee, P.A.; Stephenson, G.A.; Byrn, S.R. Cryst. Growth Des. 2003, 3, 897; (c) Hickey, M.B.; Peterson, M.L.; Manas, E.S.; Alvarez, J.; Haeffner, F.; Almarsson, Ö. J. Pharm. Sci. 2007, 96, 1090; (d) Jayasankar, A.; Reddy, S.L.; Bethune, S.J.; Rodríguez-Hornedo, N. Cryst. Growth Des. 2009, 9, 889; (e) Trask, A.V.;
Motherwell, W.D.S.; Jones, W. Int. J. Pharm. 2006, 320, 114.
50 Cheney, M.L.; Shan, N.; Healey, E.R.; Hanna, M.; Wojtas, L.; Zaworotko, M.J.; Sava, V.; Song, S.;
Sanchez-Ramos, J.R. Cryst. Growth Des. 2010, 10, 394.
51 Bak, A.; Gore, A.; Yanez, E.; Stanton, M.; Tufekcic, S.; Syed, R.; Akrami, A.; Rose, M.; Surapaneni, S.;
Bostick. T.; King, A.; Neervannan, S.; Ostovic, D.; Koparkar, A.; J. Pharm. Sci. 2008, 97, 3942.
52 Lukevits, È. Chemistry of Heterocyclic Compounds, 1995, 31, 639.
53 Andreeff, M.; Stone, R.; Michaeli, J.; Young, C. W.; Tong, W. P.; Sogoloff, H.; Ervin, T.; Kufe, D.;
Rifkind, R.A.; Marks, P. A. Blood, 1992, 80, 2604.