Research Terms
Medical Education Biochemistry Medicinal Chemistry Organic Chemistry Chemical Synthesis
1. "Kinetic and Stereochemical Effect of a Fluorine Substituent on the Cope and the Homodienyl [1,5] Hydrogen Shift Rearrangements," Dolbier, Jr., W. R.; Alty, A. C.; Phanstiel IV, O. J. Am. Chem. Soc. 1987, 109, 3046-3050.
2. "The Non-Steric Origin of Specific Disrotatory Ring Openings in Solvolyses of Cyclopropyl Derivatives. The 2-Fluorocyclopropyl Bromide system," Dolbier, Jr., W. R.; Phanstiel IV, O. Tetrahedron Letters 1988, 29, No. 1, 53-56.
3. "Fluorine- versus Methyl-Substituent Effects in the 6-methylenebicyclo[3.2.0]hept-2-ene -5-methylene-bicyclo-[2.2.1]hept-2-ene Thermal Rearrangement," Dolbier, Jr., W. R.; Phanstiel IV, O. J. Am. Chem. Soc. 1989, 111, 4907-4911.
4. "The In Situ Generation and Trapping of Some Fluorine-Substituted Ketenes," Dolbier, Jr., W. R.; Lee, S. K.; Phanstiel IV, O. Tetrahedron 1991, 47, 2065-2072.
5. "The Total Synthesis of Nannochelin: A Novel Cinnamoyl Hydroxamate-Containing Siderophore," Bergeron, R. J.; Phanstiel IV, O. J. Org. Chem. 1992, 57, 7140-7143.
6. "Reactive Processing of Blends of Functionalized Poly-(2,6-dimethyl-1,4 phenylene oxide) and Poly(butylene-terephthalate)," Hobbs, S. Y.; Stanley, T. J. ; Phanstiel IV, O. Polymer Preprints 1992, 33, No. 2, 614.
7. "The Total Synthesis of Hypusine and its (2S,9S) Diastereomer," Bergeron, R. J. ; Xia, M. X. B.; Phanstiel IV, O. J. Org. Chem. 1993, 58, 6804-6806.
8. "Macromolecular Self-Assembly of Diketopiperazine Tetrapeptides, " Bergeron, R. J.; Phanstiel IV, O. ; Yao, G. W.; Milstein, S.; Weimar, W. R. J. Am. Chem. Soc. 1994, 116, 8479-8484.
9. "A Versatile Synthesis of Desferrioxamine," Bergeron, R. J.; McManis, J. S. ; Phanstiel IV, O.; Vinson, J. R. J. Org. Chem. 1995, 60, 109-114.
10. "An Investigation of the Impact of Molecular Geometry upon Microcapsule Self-Assembly,” Bergeron, R. J.; Yao, G. W.; Erdos, G.; Milstein, S.; Gao, F.; Weimar, W. R.; Phanstiel IV, O. J. Am. Chem. Soc. 1995, 117, 6658-6665.
11. “Development of a Hypusine Reagent for Peptide Synthesis,” Bergeron, R. J.; Ludin, C.; Muller, R.; Smith, R. E.; Phanstiel IV, O. J. Org. Chem. 1997, 62, 3285-3290.
12. “A Comparison of Structure Activity Relationships between Spermidine and Spermine Analogue Antineoplastics,” with Bergeron, R. J.; Feng, Y.; Weimar, W. R.; McManis, J. S.; Dimova, H.; Porter, C.; Raisler, B.; Phanstiel IV, O. J. Med. Chem. 1997, 40, No. 10, 1475-1494.
13. “The Influence of Molecular Conformation Upon the Self-Assembly of Cyclohexane Diamide Diacids,” Bergeron, R.J.; Yao, G. W.; Erdos, G. W.; Milstein, S.; Gao, F.; Rocca, J.; Weimar, W. R.; Price, H. L.; Phanstiel IV, O. Bioorg. Med. Chem. 1997, 5 (11), 2049-2061.
14. “An Improved Synthesis of O-Benzoyl Protected Hydroxamates” Wang, Q. X.*; King, J.+; Phanstiel IV, O. J. Org. Chem. 1997, 62, 8104-8108.
15. “Total Synthesis of Acinetoferrin” Wang, Q. X.*; Phanstiel IV, O. J. Org. Chem. 1998, 63, 1491-1495.
16. “Synthesis of Exotic Soaps in the Chemistry Laboratory,” Phanstiel IV, O. ; Dueno, E.+; Wang, Q. X.* J. Chem. Ed. 1998, 75, No. 5, 612-614.
17. “Supramolecular Construction Using Diamide Diacids Containing Aromatic Amino Acids,” Phanstiel IV, O.; Price, H. L.; Torres, D.; Richardson, M.; Seconi, D.* Florida Scientist 1998, 61, Suppl. 1, 36.
18. “Vectored Antineoplastics Predicated Upon Polyamine-DNA Intercalator Conjugates,” Phanstiel IV, O.; Majmundar-Shah, S.*; Wang, L.*; Price, H. L. Florida Scientist 1998, 61, Suppl. 1, 37.
19. “Synthesis of Secondary Amines via N-(Benzoyloxy)amines and Organoboranes” Phanstiel, IV, O.; Wang, Q. X.*; Powell, D. H.; Ospina, M. P.; Leeson, B. A.+ J. Org. Chem. 1999, 64, 803-806.
21. "The Effect of Polyamine Homologation on the Transport and Cytotoxicity Properties of Polyamine-DNA Intercalator Conjugates" Phanstiel IV, O.; Price, H.L.; Wang, L.*; Juusola, J.; Kline, M.; Shah, S.M.* J. Org. Chem. 2000, 65, 5590-5599.
24. “The Influence of Polyamine Architecture on the Transport and Topoisomerase II Inhibitory Properties of Polyamine DNA-Intercalator Conjugates,” Wang, L.*; Price, H.L.; Juusola, J.; Kline, M.; Phanstiel, IV, O. J. Med. Chem. 2001, 44, 3682-3691.
25. “Synthesis and Biological Evaluation of New Citrate-Based Siderophores as Potential Probes for the Mechanism of Iron Uptake in Mycobacteria” Guo, H.*; Naser, S.A.; Ghobrial, G.; Phanstiel, IV, O. J. Med. Chem. 2002, 45, 2056-2063.
26. “Molecular modeling of the 1,1-Cyclopropane and 1,1-Cyclobutane-dicarboxamide Systems: Insights into the Self-Assembly of Diamide Diacids in Water” Breitbeil, F.; Phanstiel, IV, O. Structural Chemistry, 2002, 13, 443-453.
27. “Synthesis and Characterization of N1-(4-toluenesulfonyl)-N1-(9-anthracenemethyl)-triamines” Wang, C.; Abboud, K.A.; Phanstiel IV, O. J. Org. Chem. 2002, 67, 7865-7868.
28. “N-(Benzoyloxyamines): an investigation of their thermal stability, synthesis and incorporation into novel peptide constructs,” Nemchik, A.+; Badescu, V.*; Phanstiel IV, O. Tetrahedron 2003, 59, No. 24, 4315 – 4325.
29. “Synthesis and Biological Evaluation of N1-(anthracen-9-ylmethyl)triamines as Molecular Recognition Elements for the Polyamine Transporter,” Wang, C.; Delcros, J-G.; Biggerstaff, J.; Phanstiel IV, O. J. Med. Chem. 2003, 46, 2663-2671.
30. “Molecular Requirements for Targeting the Polyamine Transport System: Synthesis and Biological Evaluation of Polyamine-Anthracene Conjugates,” Wang, C.; Delcros, J-G.; Biggerstaff, J.; Phanstiel IV, O. J. Med. Chem. 2003, 46, 2672-2682.
31. “Defining the Molecular Requirements for the Selective Delivery of Polyamine-Conjugates into Cells Containing Active Polyamine Transporters,” Wang, C.; Delcros, J-G.; Cannon, L.+; Konate, F.*; Carias, H.+; Biggerstaff, J.; Gardner, R.A.; Phanstiel IV, O. J. Med. Chem. 2003, 46, 5129-5138.
32. “Total Synthesis of Petrobactin and Its Homologues as Potential Growth Stimuli for Marinobacter hydrocarbonoclasticus, an oil-degrading bacteria.” Gardner, R.A.; Kinkade, R.+; Wang, C. ; Phanstiel IV, O. J. Org. Chem. 2004, 69, 3530-3537.
33. “Synthesis and Biological Evaluation of new Acinetoferrin Homologues for use as Iron Transport Probes in Mycobacteria,” Gardner, R.A.; Ghobrial, G.; Naser, S.A.; Phanstiel IV, O. J. Med. Chem. 2004, 47, 4933-4940.
34. “N1-Substituent Effects in the Selective Delivery of Polyamine-Conjugates into Cells Containing Active Polyamine Transporters” Gardner, R.A.; Delcros, J-G.; Konate, F.*; Breitbeil III, F.; Martin, B.; Sigman, M.; Huang, M.; Phanstiel IV, O. J. Med. Chem. 2004, 47, 6055-6069.
35. “Synthesis and Biological Evaluation of Dihydromotuporamine Derivatives in Cells Containing Active Polyamine Transporters” Kaur, N,; Delcros, J-G.; Martin, B.; Phanstiel, IV, O. J. Med. Chem. 2005, 48, 3832-3839.
36. “Modeling the Preferred Shapes of Polyamine Transporter Ligands and Dihydromotuporamine-C Mimics: Shovel versus Hoe,” Breitbeil III, F. Kaur, N.; Delcros, J-G.; Martin,B.; Abboud, K.A.; Phanstiel, IV, O. J. Med. Chem. 2006, 49, 2407-2416.
37. Comparative Studies of Anthraquinone- and Anthracene-Tetraamines as Blockers of N-Methyl-D-aspartate Receptors. Jin, L.; Sugiyama, H.; Takigawa, M.; Katagiri, D.; Tomitori, H.; Nishimura, K.; Kaur, N.; Phanstiel, IV, O.; Kitajima, M.; Takayama, H.; Okawara, T.; Williams, K.; Kashiwagi, K.; Igarashi, K. JPET 2007, 320, 47-55.
38. Synthesis and Transfection Efficiencies of new Lipophilic Polyamines. Gardner, R.A.; Belting, M.; Svensson, K.; Phanstiel, IV, O. J. Med. Chem. 2007, 50, 308-318.
39. Synthesis and Bioevaluation of the N-(Arylalkyl)-Homospermidine Conjugates. Songqiang Xie, Pengfei Cheng, Guangchao Liu, Yuangfang Ma, Jin Zhao, Mounir Chehtane, Annette R. Khaled, Otto Phanstiel IV and Chaojie Wang. Bioorganic & Medicinal Chemistry Letters 2007, 17, 4471-4475.
40. Structure-activity Investigations of Polyamine-anthracene Conjugates and their Uptake via the Polyamine Transporter. Phanstiel, IV, O.; Kaur, N.; Delcros, J-G. Amino Acids, 2007, 33, No. 2, 305-313.
41. Lipopolyamine Treatment Increases the Efficacy of intoxication with Saporin and an Anti-cancer Saporin Conjugate. Geden, S.; Gardner, R.; Fabbrini, S.M.; Ohashi, M.; Phanstiel IV, O. Teter, K. FEBS Journal, 2007, 274, No. 18, 4825-4836.
42. Utilization of Fe3+ -Acinetoferrin Analogues as an iron source by Mycobacterium tuberculosis. Rodriguez, G. M.; Gardner, R. A.; Kaur, N.; Phanstiel IV, O. Biometals 2008, 21, 93-103.
43. A Drosophila model to identify polyamine-drug conjugates that target the polyamine transporter in an intact epithelium, Chung Tsen†§, Mark Iltis†§, Navneet Kaur†, Cynthia Bayer§, Jean-Guy Delcros‡, Laurence von Kalm§* and Otto Phanstiel IV†* J. Med Chem., 2008, 51, 324–330.
44. A Comparison of Chloroambucil- and Xylene-containing polyamines leads to improved ligands for accessing the polyamine transporter. Navneet Kaur, Jean-Guy Delcros, and Otto Phanstiel IV. J. Med. Chem. 2008, 51, 1393-1401.
45. A Delineation of Diketopiperazine self-assembly processes: Understanding the molecular events involved in Ne-(fumaroyl) diketopiperazine of L-Lys (FDKP) interactions. Navneet Kaur, Bo Zhou, Fred Breitbeil, Katherine Hardy, Kelly S. Kraft, Iva Trantcheva and Otto Phanstiel IV, Molecular Pharmaceutics, 2008, 5, No. 2, 294-315.
46. Designing the Polyamine Pharmacophore: Influence of N-substituents on the transport behavior of polyamine conjugates, Kaur, N.; Delcros, J-G.; Archer, J.; Weagraff, N.Z.; Martin, B.; Phanstiel IV, O. J. Med. Chem. 2008, 51, 2551-2560.
47. Chemoselective N-acylation via Condensations of N-(Benzoyloxy)amines and a-Keto-phosphonic acids under Aqueous Conditions. Jasbir Singh Arora, Navneet Kaur and Otto Phanstiel IV, J. Org. Chem. 2008, 73, 6182-6186.
48. Synthesis and evaluation of unsymmetrical polyamine derivatives as antitumor agents. Wang, J.; Xie, S.; Li, Y.; Guo, Y.; Ma, Y.; Zhao, J.; Phanstiel IV, O.; Wang, C. Bioorg. Med. Chem. 2008, 16, 7005-7012.
49. A Putrescine-anthracene conjugate: a paradigm for selective drug delivery. Andrew J. Palmer, Radiah A. Ghani, Navneet Kaur, Otto Phanstiel and Heather M. Wallace. Biochem. J. 2009, 424, 431-438.
50. Polyamine Transport as a Target for Pneumocystis Pneumonia Therapy. Chung-Ping Liao, Otto Phanstiel IV, Mark E. Lasbury, Chen Zhang, Shoujin Shao, Pamela J. Durant, Bi-Hua Cheng, and Chao-Hung Lee, Antimicrobial Agents and Chemotherapy 2009, 53, No. 12, 5259-5264.
51. Delivering anti-cancer agents to human leukaemic cells via polyamine transport system Heather M. Wallace, Radiah A. Ghani, Andrew J. Palmer, Navneet Kaur, and Otto Phanstiel, S55, 11th International Congress on Amino Acids, Peptides and Proteins, Aug 3-7, 2009. Amino Acids 2009, 37 (Suppl. 1):S1-S127.
52. Caenorhabditis elegans P5B-type ATPase CATP-5 operates in polyamine transport and is crucial for norspermidine-mediated suppression of RNA interference. Heinick, A. Urban, K.; Roth, S.; Spies, D.; Nunes, F.; Phanstiel IV, O.; Liebau, E. Lüersen, K. FASEB Journal 2010, 24, 206-217.
53. Design of Polyamine Transport Inhibitors as Therapeutics. Otto Phanstiel IV; Jennifer J. Archer, in Polyamine Drug Discovery, P. Woster and R.A. Casero, eds., RSC Publishing, 2012. 162-187. ISBN 9781849731904.
54. Chemoselective Amide Formation Using O-(4-Nitrophenyl)-hydroxylamines and Pyruvic Acid Derivatives. Sonali Kumar, Rashi Sharma, Megan Garcia, Joseph Kamel, Caroline McCarthy, Aaron Muth, and Otto Phanstiel, IV. J. Org. Chem. 2012, 77, 10835–10845.
55. Ant 4,4, a polyamine-anthracene conjugate, induces cell death and recovery in human promyelogenous leukemia cells (HL-60). Traquete, R.; Ghani, R.A.; Phanstiel, O.; Wallace, H.M. Amino Acids 2013, 44, 1193-1203.
56. Anthracene-polyamine conjugates inhibit in vitro proliferation of intraerythrocytic Plasmodium falciparum parasites. Niemand, J.; Burger, P.; Verlinden, B.; Reader, J.; Joubert, A.; Kaiser, A.; Louw, A.I.; Kirk, K.; Phanstiel IV, O.; Birkholtz, L-M. Antimicrobial Agents and Chemotherapy. 2013, 57, 2874-2877.
57. Putrescine importer PlaP contributes to swarming motility and urolithelial cell invasion in Proteus mirabilis. Kurihara, S.; Sakai, Y.; Suzuki, H.; Muth, A.; Phanstiel, O.; Rather, P.N. J. Biol. Chem. 2013, 288, 15668-15676.
58. Development of Flavonoid-based Inverse Agonists of the Key signaling receptor US28 of Human Cytomegalovirus. Ana Kralj, Mai-Thao Nguyen, Nuska Tschammer, Nicolette Ocampo, Quinto Gesiotto, Markus R. Heinrich, and Otto Phanstiel, IV. J. Med. Chem. 2013, 56, 5019-5032.
59. Development of Polyamine Transport Ligands with Improved Metabolic Stability and Selectivity against Specific Human Cancers. Aaron Muth, Joseph Kamel, Navneet Kaur, Allyson C. Shicora, Iraimoudi S. Ayene, Susan K. Gilmour, and Otto Phanstiel IV J. Med. Chem. 2013, 56, 5819-5828.
60. Polyamine transport inhibitors: Design, Synthesis and Combination therapies with difluoromethylornithine (DFMO). Aaron Muth, Jennifer Archer, Nicolette Ocampo, Meenu Madan, Luis Rodriguez, and Otto Phanstiel IV. J. Med. Chem. 2014, 57, 348-363.
American Chemical Society, Member; 1984 - present
Researchers at the University of Central Florida and the Lankenau Institute for Medical Research have synthesized new anti-cancer small molecules that block polyamine uptake and activate the anti-tumor immune response. Many tumors require high levels of polyamines to support their growth and survival. Additionally, high levels of polyamines can suppress the immune system, allowing tumors to evade the immune response. Polyamine blockade therapy, which inhibits both polyamine transport and polyamine biosynthesis, simultaneously suppresses tumor growth and activates immunity by reversing polyamine-mediated tumor immunosuppression.
Technical details
The lead compound is a polyamine transport inhibitor that out-competes native polyamines for binding to the polyamine transport system. Polyamine blockade therapy with this compound, and the FDA-approved polyamine biosynthesis inhibitor, DFMO, significantly lowered intracellular tumor polyamine levels in a mouse tumor model. As a result, tumor growth was significantly reduced, and the anti-tumor immune response was activated. This anti-tumor effect was T-cell dependent and included an increase in granzyme B+, IFN-?+ CD8+ T-cells and a decrease in immunosuppressive tumor infiltrating cells.
A novel polyamine blockade therapy activates an anti-tumor immune response, Oncotarget, 2017 Aug 24;8(48):84140-84152. doi: 10.18632/oncotarget.20493. eCollection 2017 Oct 13
Researchers at the University of Central Florida and the Torrey Pines Institute for Molecular Studies have identified new compounds to inhibit the growth of human cancers and parasitic infections through nutrient deprivation. The compounds inhibit the import of large neutral amino acids such as leucine and methionine.
Researchers screened molecular libraries from the Torrey Pines Institute for Molecular Studies for polyamine transport inhibition and cytotoxicity. The compounds were screened for the ability to inhibit the uptake of methionine and leucine. A lead compound was shown to reduce the intracellular levels of methionine which led to decreased intracellular levels of the polyamines spermidine and spermine, which are essential growth factors. Treatment with the compound inhibited the cell growth of a metastatic human pancreatic cancer cell line.
The research team is looking for partners to further develop the technology for commercialization.
Effectiveness demonstrated on the pancreatic ductal adenocarcinoma (PDAC) cell line in vitro..
The University of Central Florida invention comprises new compounds and synthesis methods for a spermine prodrug designed to treat symptoms of a low spermine disorder. The invention provides a new potential therapy for Snyder Robinson Syndrome (SRS). Patients with SRS have little or no spermine synthase (SMS) enzyme activity and cannot effectively make spermine from spermidine. Spermine is one of the naturally occurring polyamines and plays important roles in maintaining cell health.
Development of a Redox-Sensitive Spermine Prodrug for the Potential Treatment of Snyder Robinson Syndrome, J Med Chem. 2021 Nov 11;64(21):15593-15607. doi: 10.1021/acs.jmedchem.1c00419. Epub 2021 Oct 25. PMID: 34695351; PMCID: PMC9115777.
Researchers at the University of Central Florida and Boston University are developing polyamine transport inhibitors for use as antiviral compounds. Polyamines are required for a variety of viral processes including replication, protein synthesis, and virus-host interactions. Many viruses, including coronaviruses, have been shown to be sensitive to polyamine depletion.While targeting polyamine metabolism is a known antiviral strategy, previous studies have not focused on the use of polyamine transport inhibitors. UCF's approach is to use polyamine transport inhibitors to deplete viruses of their polyamine resources.
Technical Details: Polyamine transport inhibitors are a potential new approach for treating viral infections. UCF’s patented polyamine transport inhibitor compound was shown to block SARS-Cov2 virus infection in vitro, suggesting the virus may be dependent on polyamine import for survival. The compound is readily water soluble and is a hygroscopic salt that can be stored at 4 degrees Celsius. Additional studies focusing on polyamine transport inhibitor compounds as antivirals are underway.
Partnering Opportunity: The research team is looking for partners to develop the technology further for commercialization.
Stage of Development: Preclinical.
The University of Central Florida invention is an antimicrobial agent that weakens the defenses of gram-negative bacteria, increasing their sensitivity to antibiotics. The intensive, widespread use of antibiotics to treat bacterial infections has led to an increasing number of antibiotic-resistant bacteria. Examples are gram-negative multidrug-resistant (MDR) bacteria, such as Pseudomonas aeruginosa and Klebsiella pneumoniae. Bacterial membranes form an effective barrier to many antibiotics. In addition, the bacteria’s drug efflux pumps—transport proteins—enable the bacteria to remove toxins (antibiotics) by extruding them out of the bacterial cell.
As a solution, the UCF invention can be used to permeabilize cell membranes and to disrupt the electrical potential inside the bacteria. The action de-energizes the efflux pump and enables antibiotics to remain in the bacteria therefore, increasing the susceptibility of the bacteria to the drug.
Technical Details
The UCF invention consists of compositions and methods for using the antimicrobial action and antibiotic-enhancing properties of motuporamine derivatives (lipophilic polyamines) against gram-negative bacteria. Researchers selected motuporamines (originally isolated from the marine sponge Xestospongia exigua) for their amphiphilic architectures that comprise a large hydrophobic macrocycle with an appended polyamine motif. The motuporamine derivatives were able to disrupt the proton gradient, effectively de-energizing the efflux pump. Also, the researchers found that combining one or more polyamine compounds with antibiotics enables the reduction in doses of both the polyamine compound and antibiotic to ameliorate potential adverse side effects. In one example, motuporamine derivatives, 6a (MOTU-CH2-33) and 6b (MOTU-CH2-44) exhibited excellent antimicrobial activities against many species, including the multidrug-resistant E. aerogenes EA289.
The team also investigated whether derived polyamine agents could restore the potency of the antibiotic doxycycline at well below its minimum inhibitory concentration (MIC). For example, they found that the MIC of doxycycline against P. aeruginosa PAO1 was 16 µg/mL. Yet, using the invention’s polyamine derivatives with doxycycline at a significantly lower concentration (2 µg/mL) restored doxycycline activity against E. aerogenes EA289, P. aeruginosa PAO1, and K pneumoniae KPC2-ST258.
Partnering Opportunity
The research team is seeking partners for licensing and/or research collaboration.
Stage of Development
Motuporamine derivatives tested against various bacterial strains in vitro.
Motuporamine Derivatives as Antimicrobial Agents and Antibiotic Enhancers against Resistant Gram-Negative Bacteria, ChemBioChem. 2017 Feb 1;18(3):276-283.
Antibiotic Adjuvants: Make Antibiotics Great Again!, Journal of Medicinal Chemistry 2019 62 (19), 8665-8681 DOI: https://doi.org/10.1021/acs.jmedchem.8b01781