Three Trees in Woods.  While the thicket of triazine dendrimers has grown steadily over the last eight years, the work revolves around three major intertwined themes; synthesis, drug delivery, and materials science.   At times, application drives synthesis.  At other times, the latter enables the former.  Citations are provided for more interested readers.  Current active projects include:

DNA and RNA Delivery – This project focuses on long term gene and RNA therapy as well as the discovery of new transfection agents.

Reconstituting Biological Activities from Other Dendrimer Platforms – Understanding the molecular basis for dendrimer activity requires synthesis and hypothesis-driven target selection.

Heavy Metal Sequestration – This project lies at the interface of inorganic and dendrimer chemistry.

Chemotherapy – Designing dendrimers to open up new therapeutic windows for paclitaxel-based and camptothecin-based treatments requires an interdisciplinary approach to science.

Anti-infectives/Anti-sepsis Drugs – Can dendrimers play a role in whole-world medicine?

 

A historical overview of our work follows based on the three themes identified above.

Synthesis.   Our earliest efforts employed convergent routes to targets with an initial proof of concept1 extended to generation five dendrons.2 The exploitation of reactivity Treesdifferences of triazines was a very early goal.  The first targets displayed one or two surface reactive sites.3  Variation of the core (disulfide) and interior linking groups followed with the latter family displaying varied hydrogen bonding capabilities as reflected in differences in association in organic solvents.4,5  Efforts to improve methods by judicious choice of diamines6,7 and more elaborate reactive peripheries were explored for fancy,8 potential function9 and intended purpose including thiol-disulfide exchange.10  Limitations with convergent synthesis has led us to more recently revisit divergent routes to diversity,11,12 and to do so quite effectively and at kilogram scale13 validated in part by outside parties.14,15 These efforts continue to be a vital component of our research enterprise.

 

Drug Delivery.  Synthetic targets and problems are, at least in part, chosen with respect to our interest in drug delivery.  We initially approached this challenge considering both noncovalent association and covalent attachment of drugs.  Examples of the former included efforts with indomethacin and methotrexate,16 while oligonucleotides,17 peptides,18 fluorescent model compounds,19 paclitaxel20 and camptothecin21 are representative of the latter.  The success of these constructs in cell culture led to preliminary, collaborative in vivo experiments that probed toxicity22,23 and the attenuation of drug activity,24 immunological properties,25 and biodistribution.26  Currently, more extensive studies are underway with specific diseases in mind including chemotherapy with paclitaxel25,26 as well as gene delivery.27,28  We envision these efforts to capture more and more of our energies.

 

Materials Science.   Our efforts in materials science have included investigations Kids plant a treeof dendrimer-clay hybrids29 and their ability to sequester atrazine.30  The ability of organic resins to support dendrimer growth and capture small molecules both covalently and noncovalently has been probed using Merrifield resins,31 thermoresponsive polymers,32 and polystyrene33 including efforts to regenerate it.34  These materials have been investigated as role of building blocks in hyperbranched grafts.35 Composite materials with intended use in separation science of gases have been pursued with inorganic supports including silica gels,36 SBA-15,37 MCM-4,38 alumina39 and ceramics.40

 

Other Shrubbery.  As we move toward specific applications, especially in drug delivery and devices, our needs for analytical chemistry have grown from dabble41 to areas of high intensity42,43.  This trend will undoubtedly continue.

 

1. Dendrimers Based on Melamine. Divergent and Orthogonal, Convergent Syntheses of a G3 Dendrimer.
Zhang, W.; Simanek, E.E. Org. Lett. 2000, 2, 843-845.

2. Synthesis and Characterization of Higher Generation Dendrons Based on p-Aminobenzylamine. Evidence for Molecular Recognition of Cu(II). Zhang, W.; Simanek, E.E.; Tetrahedron Lett. 2001, 42, 5355-5357.

3. Orthogonal, Convergent Syntheses of Dendrimers Based on Melamine with One or Two Surface Sites for Manipulation. Zhang, W.; Nowlan, D.T.III; Thomson, L.M.; Lackowski, W.M.; Simanek, E.E. J. Am. Chem. Soc. 2001, 123, 8914-8922.

4. Synthesis and Characterization of Anionic Triazine Dendrimers with a Labile Disulfide Core.Zhang, W.; Chouai, A.; Simanek, E.E. Isr. J. Chem. 2009, 49, 23-30.

5. Structure-Activity Relationships in Dendrimers Based on Triazines: Gelation Depends on Choice of Linking and Surface Groups. Zhang, W.; Gonzalez, S.O.; Simanek, E.E. Macromolecules 2002, 35, 9015-9021.

6.   Chemoselective building blocks for dendrimers from relative reactivity data. Steffensen, M.B.; Simanek, E.E.Org. Lett. 2003, 5, 2359-2361.

7. Identification of Diamine Linkers with Differing Reactivity and their Application in the Synthesis of a Melamine Dendrimers  Moreno, K.X.; Simanek, E.E. Tetrahedron Lett. 2008, 49, 1152-1154.

8. Synthesis and Manipulation of Orthogonally Protected Dendrimers: Building Blocks for Library Synthesis. Steffensen, M.B.; Simanek, E.E. Angew. Chem. Int. Ed. 2004, 43, 5178-5180.

9. Toward the Next-Generation Drug Delivery Vehicle: Synthesis of a Dendrimer with Four Orthogonally ReactiveGroups. Lim, J.; Simanek, E.E. Molec. Pharm. 2005, 2, 273-277.

10. Triazine Dendrimers with Orthogonally Protected Amines on the Periphery. Masking Amines with Dde andBOC Groups Provides an Alternative to Carrying Protected Alcohols and Disulfides through an IterativeSynthesis. Umali, A.; Crampton, H.; Simanek, E.E. J. Org. Chem. 2007, 72, 9866-9874.

11. A Divergent Route to Diversity in Macromolecules. Hollink, E.; Simanek, E. E. Org. Lett. 2006, 8, 2293-2295.

12. A Divergent Route towards Single-Chemical Entity Triazine Dendrimers with Opportunities for Structural Diversity. Crampton, H.; Hollink, E.; Perez, L. M.; Simanek, E. E. New J. Chem. 2007, 31, 1283-1290

13. Kilogram-Scale Synthesis of a Second Generation Dendrimer Based on 1,3,5-Triazine Using Green andIndustrially Compatible Methods with a Single Chromatographic Step. Chouai, A.; Simanek, E.E.; J. Org.Chem. 2008, 73, 2357-2366.

14. Synthesis of 2-[3,3'-Di-(tert-butoxycarbonyl)-aminodipropylamino]-4,6,-dichloro-1,3,5-triazine as a monomerand 1,3,5-[tris-piperazine]-triazine as a core for the large scale synthesis of melamine (triazine) dendrimers. Choaui, A.; Venditto, V.; Simanek, E.E. Org. Syn. 2009, 86, 141-150.

15. Large scale, green synthesis of a generation-1 melamine (triazine) dendrimer. Chouai, A.; Venditto, V.J.; Simanek, E.E. Org. Syn. 2009, 86, 151-160.

16. Triazine Dendrimers for Drug Delivery: Evaluation of Solubilization Properties, Activity in Cell Culture, and In Vivo Toxicity of a Candidate Vehicle. Zhang, W.; Jiang, J.; Qin, C.; Thomson, L.M.; Parrish, A.R.; Safe,S.H.; Simanek, E.E. Supramol. Chem. 2003, 15, 607-615.

17. Synthesis and Characterization of DNA-Dendrimer Conjugates. Bell, S.A.; McLean, M.E.; Oh, S.-K.; Tichy, S.E.; Corn, R.M.; Crooks, R.M.; Simanek, E.E. Bioconj. Chem. 2003, 14, 488-493.

18. Preparation of Multivalent Dendrimers Through Thiol-disulfide Exchange. Umali, A.P.; Simanek, E.E. Org. Lett.2003, 5, 1245-1247.

19. Evaluation of Multivalent Dendrimers Based on Melamine: Kinetics of Thiol-Disulfide Exchange Depends on the Structure of the Dendrimer. Zhang, W.; Tichy, S.E.; Pérez, L.M.; Maria, G.; Lindahl, P.A.; Simanek, E.E. J. Am. Chem. Soc. 2003, 125, 5086-5094.

20. Synthesis of Water Soluble Dendrimers Based on Melamine Bearing Sixteen Paclitaxel Groups.Lim, J.; Simanek, E.E. Org. Lett. 2008, 10, 201-204.

21. Intercepting triazine dendrimer synthesis with nucleophilic pharmacophores as a general strategy toward drug delivery vehicles. Venditto, V.J.; Allred, K.; Allred, C.D.;Simanek, E.E. Chem. Comm. 2009, Accepted.

22. In vivo evaluation of a triazine dendrimer: a potential vehicle for drug delivery. Neerman, M.R.; Zhang, W.; Parrish, A.R.; Simanek, E.E. Int. J. Pharm. 2004, 281, 129-132.

23. Cytotoxicty, Hemolysis and Acute In Vivo Toxicity of Dendrimers Based on Melamine, Candidate Vehicles for Drug Delivery. Chen, H.-T.; Neerman, M.F.; Parrish, A.R.; Simanek, E.E. J. Am. Chem. Soc. 2004, 126, 10044-10048.

24. Attenuation of Drug Toxicity Using Dendrimers Based on Melamine, Candidate Vehicles for Drug Delivery. Neerman, M.F.; Chen, H.-T.; Parrish, A.R.; Simanek, E.E. Molec. Pharm. 2004, 1, 390-393.

24. Biological evaluation of dendrimers based on melamine. Neerman, M. F.; Umali, A. P.; Chen, H.-T.; Waghela, S. D.; Parrish, A. R.; Simanek, E. E. J. Drug Del. Sci. Tech. 2005, 15, 31-40.

25. The Role of Size and Number of Polyethyleneglycol Chains on the Biodistribution and Tumor Localization of Triazine Dendrimers. Lim, J.; Guo, Y.; Rostollan, C.L.; Stanfield, J.; Hseih, J.-T.; Sun, X.; Simanek, E.E. Molec. Pharm. 2008, 5, 540-547.

25. Design, Synthesis, and Characterization of Triazine Dendrimers Bearing Paclitaxel linked by Ester and Ester/Disulfide Linkages. Lim, J.; Chouai, A.; Lo, S-T.; Liu, W.; Sun, X.; Simanek, E.E. Bioconj. Chem. 2009, Submitted.

26.  Work with the Nanotechnology Characterization Laboratory.  Details available on request.

27. Polycationic triazine-based dendrimers: Effect of peripheral groups on transfection efficiency. Mintzer, M.A.; Merkel, O.M.; Kissel, T.; Simanek, E.E. New J. Chem. 2009, In press.

28. Triazine dendrimers as non-viral gene delivery systems: Effects of molecular structure on biological activity. Merkel, O. M.;Mintzer, M. A.; Sitterberg, J.; Bakowsky, U.; Simanek, E. E.; Kissel, T. Bioconj. Chem. 2009, Submitted.

29.  Dendritic Surfactants Show Evidence for Frustrated Intercalation: A New Organoclay Morphology. Acosta, E.J.; Deng, Y.; White, G.N.; Dixon, J.B.; McInnes, K.; Senseman, S.A.; Frantzen, A.S.; Simanek, E.E. Chem. Mater. 2003, 15, 2903-2909.

30. Melamine-based organoclay to sequester atrazine. Neitsch, S. L.; McInnes, K. J.; Senseman, S. A.; White, G. N.; Simanek, E. E. Chemosphere 2006, 64, 704-710.

31. Removal of Atrazine from Water Using Reactive Resins. Acosta, E.J.; Steffensen, M.B.; Tichy, S.E.; Simanek, E.E. J. Agric. Food Chem. 2004, 52, 545-549.

32. Latent Solid-Phase Extraction Using Thermoresponsive Soluble Polymers. Gonzalez, S.O.; Furyk, S.; Li, C.; Tichy, S. E.; Bergbreiter, D. E.; Simanek, E. E. J. Poly. Sci. A. 2004, 42, 6309-6317.

33. Piperidine-Functionalized Supports Sequester Atrazine from Solution. Hollink, E.; Tichy, S. E.; Simanek, E.E. Ind. Eng. Chem. Res. 2005, 44, 1634-1639.

34. Strategies for protecting and manipulating triazine derivatives. Hollink, E.; Simanek, E. E.; Bergbreiter, D. E. Tetrahedron Lett. 2005, 46, 2005-2008.

35. New synthetic methods for the formation of basic, polyvalent, hyperbranched grafts. Bergbreiter, D. E.; Simanek, E. E.; Owsik, I. J. Poly. Sci. A 2005, 43, 4654-4665.

36. Synthesis, characterization, and application of melamine-based dendrimers supported on silica gel. Acosta, E.J.; Gonzalez, S. O.; Simanek, E. E. J. Poly. Sci. A 2005, 43, 168-177.

37. Engineering Nanospace: Iterative Synthesis of Melamine-based Dendrimers on Amine-functionalized SBA-15 Leads to a Stepwise Reduction in Pore Volume. Acosta, E.; Carr, S.C.; Simanek, E.E.; Shantz. D.F. Adv. Mater. 2004, 16, 985-989

38. Engineering nanospaces: Ordered mesoporous silicas as model substrates for building complex hybrid materials. Ford, D. M.; Simanek, E.E.; Shantz, D.F. Nanotechnology 2005, 16, 458-475.

39. Nanocomposite membranes of chemisorbed and physisorbed molecules on porous alumina for environmentally important separations. Javaid, A.; Gonzalez, S. O.; Simanek, E. E.; Ford, D. M. J. Membrane Sci. 2006, 275, 255-260.

40. Reverse-Selective Membranes formed by Dendrimers on Mesoporous Ceramic Supports. Yoo, S.; Yeu, S.; Sherman, R. L.; Shantz, D.E.; Simanek, E.E.; Ford, D.A. J. Membrane Sci. 2009, 334, 16–22

A-Series References in Analytical Chemistry
41. Conformational Analysis of Triazine Dendrimers: Using NMR Spectroscopy to Probe the Choreography of a Dendrimer’s Dance. Moreno, K.X.; Simanek, E.E. Macromolecules 2008, 41, 4108-4114.

42. Electrophoretic Behavior of Anionic Triazine and PAMAM Dendrimers: Methods for Improving Resolution and Assessing Purity Using Capillary Electrophoresis. Lalwani, S.; Venditto, V.J.; Chouai, A.; Rivera, G.E.; Shaunak, S. Simanek, E.E. Macromolecules, 2009, 42, 3152–3161.

43. Mimicking PAMAM Dendrimers with Ampholytic, Hybrid Triazine Dendrimers: A Comparison of Dispersity and Stability. Lalwani, S.; Chouai ,A.; Perez,L.M.; Santiago,V.; Shaunak,S. Simanek, E.E. Macromolecules, 2009, Accepted.

Reviews Not Cited

R1. The Eight Year Thicket of Triazine Dendrimers. Strategies, Targets, and Applications. Simanek, E.E.; Hanan A.; Lalwani, S.; Lim, J.; Mintzer, M.; Venditto, V.J.; Vittur, B. Proc. Royal Soc. A. 2009, In press.

R2. Synthetic Vectors for Gene Delivery. Mintzer, M.; Simanek, E.E. Chem. Rev. 2009, 109, 259-302.

R3. Dendrimers as drug delivery vehicles: Non-covalent interactions of bioactive compounds with dendrimers. Crampton, H.; Simanek, E. E. J. Poly. Int. 2007, 56, 489-496.

R4. Dendrimers based on [1,3,5]-triazines. Steffensen, M. B.; Hollink, E.; Kuschel, F.; Bauer, M.; Simanek, E.E. J. Poly. Sci. A 2006, 44, 3411-3433.

R5. Engineering Nanospaces: OMS/Dendrimer Hybrids Possessing Controllable Chemistry and Porosity. Yoo, S.; Lunn, J. D.; Gonzalez, S.; Ristich, J. A.; Simanek, E. E.; Shantz, D. F. Chem. Mater. 2006, 18, 2935-2942.