Haim Leader CV & Publications

Curriculum Vitae

Education

Brief Chronology of Employment

Research interests and major fields of expertise

    Design, synthesis and structural elucidation of drugs and compounds related to the cholinergic system particularly muscarinic antagonists, antidotes and reactivators against OP ChEs inhibitors.
Sterospecific synthesis of chiral organophosphate(OP) insecticides.

    Studies of the physical and chemical properties of acyl phosphonic acid derivatives which are candidates for developing novel anti osteoporosis and anti osteolytic bone diseases drugs.

     Design and synthesis of binary function drugs: carbamoyl and pyridostigmine-aprophe analoges (“Carbaphens “ and “Pyridophens”) which are both antimuscarinic and reversible anti- cholinesterase (ChE).
    Synthesis and characterization of charged phosphonyl-pyridine-oximes (POX’s), potent acetyl cholinesterase(AChE) inhibitors which are labile intermediate formed during oxime (e.g 2-PAM) induced reactivation of phosphonylated cholinesterases.

     Developing novel pro-drug strategy for the treatment of OP ChEs intoxication: dihydro 2-PAM, (pro 2-PAM), after crossing the blood brain barrier (BBB), oxidizes in vivo back to 2-PAM and represents the first non-invasive means of administering a CNS therapeutic for the deleterious effects of OP poisoning by reactivation of CNS AChE.

    Studies aimed to evaluate the potential of using organohosphorous hydrolases (OPH) and phosphorous triesterases (PTE) enzymes as catalytic scavengers in OP intoxication.

     Developing a novel technology of purification of proteins using polyurethane immobilized ligands as macroaffinity ligand ”sponges”.

     Catalytical detoxification of OP toxic agents: Sterospecific synthesis of chiral fluorogenic organophosphate inhibitors of acetycholinesterase (AChE) homologous in structure to nerve agents which provide useful probes for high throughput screening of mammalian paraoxonase (PON1) libraries generated by directed evolution of an engineered PON1 variant with wild- type like specifity.

    Design and synthesis of multifunctional ligands bearing hydroxamate groups with fluorogenic probes which are useful in coordination of self-assembly of organic multilayer on gold.

    Mass spectrometry (MS), protons (H¹) carbon (C¹³) and phosphrous(P³¹) nuclear magnetic resonance (NMR) are the main methodological analytical tools in my research.

Collaboration in the US

Prof. John Casida, University of Caifornia, Berkeley, Berkeley CA.
Prof. Palmer Tailor, University of California San Diego, CA.
Dr. B.P. Doctor, Head, Division of Biochemistry, Walter Reed Army Institute of Research
(WRAIR),Silver Spring MD. Dr Richard K. Gordon, Head, Department of Biochemical
Pharmacology, WRAIR, Silver Spring, MD.

List of Publications

1. Leader, H. Partial hydrogenolysis of cyclopropylstyrene system. M.Sc. thesis, Hebrew University Jerusalem, 1958. (Supervisor: Prof. Sarel, S.).
2. Breuer, E., Leader, H. and Sarel, S. Paper chromatography of 2,4-dinitrophenylhydrazones of aromatic ketones. Bull. Res. Counc. Israel. A. 91, 43, 1960.
3. Sarel, S. and Leader, H. The synthesis of phenylated aziridinones. J. Am. Chem. Soc., 82, 4752, 1960.
4. Sarel, S. and Leader, H. The synthesis and properties of arylated α-lactams. The Israel chemical society. 42,1961.
5. Pelchowitz, Z. and Leader, H. O,O-dialkyl methylphosphonothionates and O-alkyl methylphosphonothioic acids. The Israel chemical society, 42, 1961.
6. Pelchowitz, Z., Leader, H.,Cohen, S. and Balderman, D. The preparation of O,O-dialkyl and O-alkyl hydrogen methylphosphonothioates. J. Chem. Soc., 3824, 1962.
7. Pelchowitz, Z. and Leader, H. Organophosphorous compounds part v: The preparation of O-alkyl hydrogen methylphosphonothioates. J. Chem. Soc., 3320, 1963.
8. Leader, H. Studies on the total synthesis of heterocyclic systems related to Lysergic acid. PhD. thesis, The Hebrew University, Jerusalem, 1970. (Supervisors: Prof. Felix Bergmann and Prof. Zvi Pelach).
9. Leader, H., Kabra, P.H., Spencer, C.L. and McChesney, J.D. Geometrically defined analgetics. 10^th Midwest ACS. regional meeting, the University of Iowa, Iowa city, Iowa, 1974.
10. Leader, H., Kabra, P.H., Spencer, C.L. and McChesney, J.D. Geometrically definedanalgetics. 12^th Annual medical chemistry meeting in miniature, the University of Kansas, Lawrence Kansas., 1974.
11. Granoth, I., Alkabetz, R., Segall, Y., Rachman, E. and Leader, H. Novel specific carbon-carbon bond formation: Substituent solvent effects associated with hydride addition to aromatic olefins. J.C.S., Chem. Comm., 348, 1975.
12. Granoth, I., Segall, Y., Leader, H. and Alkabetz, R. Chemical consequences of hydride addition to aromatic olefines. J. Org. Chem., 41, 3682, 1976.
13. Granoth, I., Segall, Y. and Leader, H. Product control in nucleophilic substitution at terahedral phosphorous by relative apicophilicity of the nucleophile. J.C.S., Chem. Comm., 74, 1976.
14. Granoth, I., Segall, Y. and Leader, H. 5,10-Dihydrodibenzo[b,e]phosphorin: unique sterochemistry and reactivity. Israel Chem. Soc., 44, 1977.
15. Granoth, I., Segall, Y. and Leader, H. Stereoselective reduction and alcohol deoxygenation by a phosphine in the 5,10-dihydrodibenzen[b,e]phosphorine series. J. Chem. Soc. Perkin I, 456, 1978.
16. Ashani, J. and Leader, H. The formation of covalent intermediate during the inhibition of acetylcholesterase with 1,3,2-dioxaphosphorinane-2-oxides. Israel J. Med. Sci., 15, 89, 1979.
17. Rachaman, E.S., Ashani, J., Leader, H., Granoth, I., Edery, H. and Porath, y. Suger-Oximes; New potential antidotes against O.P. poisoning. Drug Res. (Atzneim-Forsch.), 29, 875, 1979.
18. Ashani, J. and Leader, H. The formation of unstable covalent intermediate during the inhibition of eel acetylcholinesterase with 1,3,2-dioxphosphorinane-2-oxides. Biochemical J., 177, 781, 1979.
19. Campbell, A.L., Leader, H., Sierra, M.G., Spencer, C.L. and McChesney, J.D. Substituted 4a-methyloctahydrophenanthrene: Conformation and proton magnetic resonance characteristics. J. Org. Chem., 44, 2755, 1979.
20. Campbell, A.L., Leader, H., Spencer, C.L and McChesney, J.D. Stereoselective synthesis of 4a-methyloctahydrophenanthrenes. A novel approach 1: C-2 and C-3 substituted series. J. Org. Chem., 44, 2746, 1979.
21. Gabor, G. and Leader, H. Quantitative determination of Etonitazene. Anal. Biochem., 106, 377, 1980.
22. Granoth, I., Segall, Y., Waysbort, D., Shirin, E. and Leader, H. Hydroxyphosphorane intermediates in substitution reactions at phosphorus in acyclic phosphonofluoridates: Evidence from nuclear magnetic resonance. J. Am. Chem. Soc., 102, 4523, 1980.
23. Leader, H., Raveh, L., Bruckstein, R., Spiegelstein, M. and Ashani, Y. Reversible masking of acetylcholinesterase by covalent phosphorylation in the presence of a novel cyclic phosphate ester. ACS Symposium series on phosphorous chemistry 171, 179, ACS Washington DC. 1981. ( Eds: Quinn ,L.D. and Verkade, J.K. ).
24. Leader, H. and Casida, J.E. Resolution and biological activity of the chiral isomers of O-(4-bromo-2-chlorophenyl) O-ethyl S-propyl phosphorothioate (profenofos insecticide). J. Agric. Food Chem., 30, 546, 1982.
25. Leader, H., Ashani, Y., Spiegelstein, M., Bruckstein, R. and Nissenkorn. Cyclic organophosphates as possible anticholinesterase drugs for treatment of cholinergic disorders. North american chemistry symposium, University of Toronto, Canada, June 1982.
26. Ashani, Y., Leader, H., Raveh, L., Bruckstein, R. and Spiegelstein, M. In vitro and in vivo protection of acetylcholinesterase against organophosphate poisoing by pretreatment with a novel derivate of 1,3,2-dipxaphosphorinane - 2-oxide. J. Med. Chem., 28,145, 1983.
27. Hirashima, A., Leader, H., Holden, I.and Casida. J.E. Resolution and stereoselective action of Sulprofos and related S-propyl phosphorodithioates. J. Agric. Food Chem., 32, 1302, 1984.
28. Gonzalez-Sierra, M., Leader, H. and McChesney, J.D. Stereoselective synthesis of 4a-methyloctahydrophenanthrenes: A novel approach 2 : C-1 substituted series. J. Org. Chem., 50, 4450, 1985.
29. Ashani, Y., Leader, H., Richards, M. and Shakked, Z. Inhibition of cholinesterase by 1,3,2-dioxaphosphorinane - 2-oxide ester of 3-trimethylamino phenol. 1^st Meeting of Israeli life science association, 1983.
30. Breuer, E., Karaman, R., Leader, H., Goldblum, A. and Moshe, R. Some new reactions of acetyl phosphonic acids. 10^th. International Conference on Phosphorous Chemistry, Bonn, W. Germany, 1986.
31. Breuer, E., Karaman, R., Leader, H., Goldblum, A. and Moshe, R. Acylphosphonic acid derivatives: New precursors for low coordination phosphorus species. Phosphorus and Sulfur, 30, 113, 1987.
32. Breuer, E., Karaman, R., Leader, H. and Goldblum, A. Fragmentation of acylphosphonates: New ptecursors for dicoordinated phosphorus species. Phosphorus and Sulfur, 33, 61, 1987.
33. Breuer, E., Karaman, R., Leader, H.and Goldblum, A. Phosphorylation of alcohols throuh the acid catalyzed fragmentation of -oximinophosphonates. J.C.S., Chem. Comm., 671, 1987.
34. Breuer, E., Karaman, R., Leader, H. and Goldblum, A. Alkylation of sulfonic acids by trialkyl phosphites. A new synthesis of sulfonate esters. Chem. & Ind., 857, 1987.
35. Smejkal, R.M., Leader, H., Gordon, R.K. and Chiang, P.K. Structure activity relationship of aprophen analogs. J. Cell Biol., 107, 1708, 1988.
36. Leader, H., Wolf, A.D., Smejkal, R.M., Covington, J.W., Payne, C.S., Padilla, F.N., Philiphs, L.R., Gordon, R.K. and Chiang, P.K. Binary prophylactic antidote for organophosphate poisoning: An aprophen analog that is both an antimuscarinic and a carbamate. FASEB J., 2, 2877, 1988.
37. Newman, A. H., Leader, H., Covington, J.W., Oleshansky, M. and Chiang, P.K. Aprophit: A potential irreversible antagonist for muscarinic receptor. Soc. Neurosci. 14, 435.4, 1988.
38. Smejkal, R.M., Leader, H., Payne, C.S., Wolf, A.D., Brown, N.D., Gordon, R.K. and Chiang, P.K. Carbamyl-aprophen analogs function as both antimuscarinics and anticholinesterases. Soc. Neurosci., 14, 530.23, 1988.
39. Leader, H., Smejkal, R.M., Covington, J.W., Padilla, F.N., Gordon, R.K. and Chiang, P.K. Muscarinic receptor subtype specificity of cyclohexyl-aprophen analogs. The pharmacologist, 59, 1, 1988.
40. Leader, H., Payne, C.S., Smejkal, R.M., Padilla, F.N.,Saeed, M.A., Wolf, A.D., Brown, N.D., Gordon, R.K. and Chiang, P.K. Carbamoyl-aprophen: Design and synthesis of antimuscarinic-anticholinesterase binary prodrugs. Ohalo Conference, Eilat, Israel,1988.
41. Breuer, E., Karaman, R.,Gibson, D., Leader, H. and Goldblum, A. -Hydroxyiminophosphonic acids. New types of phosphorylating agents through monomeric metaphosphate. J.C.S., Chem. Comm., 504, 1988.
42. Breuer, E., Karaman, R., Goldblum, A. and Leader, H. Sulfonic acid induced fragmentation of dialkyl acylphosphonates : Formation of alkyl carboxylates and alkyl sulfonates. J. Chem. Soc., Perkin Trans., 2, 2029, 1988.
43. Breuer, E., Karaman, R., Goldblum, A., Gibson, D., Leader, H., Potter, B.V.L. and Cummins, J.H. α-Oxyiminophosphonates: Chemical and physical properties. Reactions, theoretical calculations and crystal structures of (E) and (Z) –dimethyl α-hydroxyiminobenzylphosphonates. J. Chem. Soc., Perkin., 1, 3047, 1988.
44. Leader, H., Smejkal, R.M., Payne, C.S., Padilla, F.N., Doctor, B.P., Gordon, R.Kand Chiang, P.K. Binary antidotes for organophosphates poisoning: Aprophen analogsthat are both antimuscarinic and carbamates. J. Med. Chem., 32, 1522, 1989.
45. Brown, N.D., Smejkal, R.M., Leader, H., Gordon, R.K., Phillips, L.R. and Chiang, P.K. Isolation and identification of a hydroxylated metabolite of aprophen with antimuscarinic activity. Proceeding of the med. defense bioscience review, 1989.
46. Karaman, R., Goldblum, A., Breuer, E. and Leader, H. Acylphosphonic acids and methyl hydrogen acylphosphnates. Physical and chemical properties and theoretical calculations. J. Chem. Soc. Perkin., 1, 765, 1989.
47. Katzhendler, J., Karaman, R., Gibson, D., Leader, H. and Breuer, E. Fragmentation of methyl hydrogen -hydroxyiminophosphonates to monomeric methyl metaphosphate: Stereochemistry and mechanism. J. Chem. Soc., Perkin Trans., 2, 589, 1989.
48. Newman, A.H., Covington, J.C., Oleshansky, M., Jackson, B.W., Weissman, B.A., Leader, H. and Chiang, P.K. Aprophit: An irreversible antagonist for muscarinic receptors. Biochem. Pharmac., 40, 1357, 1990.
49. Breuer, E., Schlossman, A., Sefadi, M., Gibson, D., Chorev, M. and Leader, H. Stereoselectivity in fragmentation and rearrangement of -hydroxyimino -phosphinates and phosphonates. A synthetic approach to acylphosphon and phosphor–amidates. Crystal structures of methyl (E)-α-hydroxyimino- benzylphenylphosphinate and methyl benzoylphenylphosphonoamidate. J. Chem. Soc., Perkin Trans., 1, 3263, 1990.
50. Brown, N.D., Phillips, L.R., Leader, H. and Chiang, P.K. Isolation and identification of β-hydroxyethylaprophen: A urinary metabolite of aprophen in rats. J. of Chromatography. 563,466, 1991.
51. Leader, H., Gordon, R.K., Baumgold, R.K., Boyd, V.L., Newman, A.H., Smejkal, R.M. and Chiang, P.K. Muscarinic receptor specificity of N,N-dialkylaminoalkyl 2-cyclohexyl-2-phenylpropionates: Cyclexphens. J. Med. Chem., 35, 1290, 1992.
52. Leader, H., Gordon, R.K., Baumgold, R.K., Smejkal, R.M. and Chiang, P.K. Receptors subtype selectivity of cyclohexyl-aprophen antimuscarinics. Medical Defence Bioscience review, 569, 1991.
53. Karle, J.M., Karle, I.L., Leader, H., Breuer, E., Newman, A.H., Gordon, R.K. and Chiang, P.K. Relationship of crystal structure of N,N-dimethylaminopropyl 2,2-diphenylpropionate HCl to antimuscarinic activity. J. of Cryst. Spec. Res., 22, 485, 1992.
54. Wolfe, A.D., Doctor, B.P., Chiang, P.K. and Leader, H. The effect of the monoclonal antibody AE-2 on inhibition of fetal bovine serum Acetylcolinesterase (FBS-AChE) by organophosphates and carbamates. Multidisciplinary approaches to choliesterase functions, Oholo conference, Eilat, 1992.
55. Amitai,G., Raveh,L., Rabinovitz, I., Chen, R., Cohen, G., Zomber,G. , Harari, Y., Adani, R., Manistersky , B. and Leader,H. AB-21: A novel bisquaternary dioxime for the treatment of organophosphorus poisoning. Proceedings of the 23^rd annual meeting of the society for neuroscience, 19 , 918 , 1993.
56. Amitai, G., Rabinovitz, I., Raveh,L., Cohen, G., Zomber, G., Harari, Y., Adani, R., Manistersky , B. and Leader,H. Newly designed bisquaternary oxime as antidote for OP poisoning – in vitro and in vivo studies, Proceedings of the 2^nd annual meeting of the Israel society for neuroscience, 68, 1993.
57. Leader, H., Brown, N.D., Philips, L.R., Gordon, R.K., Smejkal, R.M. and Chiang, P.K. Synthesis of N-ethyl-N-(-hydroxyethyl)aminoethyl 2,2-diphenyl propionate : A metabolite of aprophen with antimuscarinic activity. J. Pharm. Sci., 82, 653, 1993.
58. Amitai, G., Chen, R., Cohen, G., Zomber, G., Adani, R., Manistersky , B., Raveh,L. and Leader, H. Antidotal efficacy of bis-quaternary oximes against soman and tabun poisoning in various species. Proceeding of the med. defense bioscience review, 2, 527, 1993.
59. Ashani, Y., Vincze, A., Manistersky, B. and Leader, H. Chemical and biological studies on the conversion of alkylating agents to phosphorothiolates and their subsequent sequestration by cholinesterases. Phosphorus, Sulfur, and Silicon, 109, 377, 1966.
60. Ashani, Y., Leader, H., Rotschild, N. and Dosoretz, C. Bioscavengers of environmental toxins: Combined effect of an organophosphorous hydrolase and oxime reactivator on the rate of reactivation of phosphorylated acetylcholinesterase. 3^rd Polish-Israel symposium on peptides and proteins, Warswa, Polland, 1997.
61. Leader, H., Vincze, A., Rothschild, N., Dosoretz, C. and Ashani, Y.Sequestration of toxic phosphorylated oximes by stoichiometric and catalytic scavengers. The 6^th international meeting on cholinesterases. La Jolla, California, USA, 1998.
62. Ashani, Y., Leader H., Rothschild, N. and Dosoretz, C. Combined effect of organophosphorus hydrolase and oxime on the rate of reactivation of diethylphosphoryl-acetylcholinesterase conjugates. Biochem. Pharmac., 55,159, 1998.
63. Luo, C., Ashani, Y., Saxena, A., Leader, H., Maxwell, D.M., Taylor, P. and Doctor, B.P. Acceleration of oxime-induced reactivation of OP-inhibited AChE by quaternary ligands. The 6^th international meeting on cholinesterases. La Jolla, California, USA 1998.
64. Leader, H., Rothschild, N., Dosoretz, C. and Ashani, Y. Organophosphorous hydrolases as antidotes against organophosphates toxicity: A phosphorylated oxime is substrate of bacterial phosphotriesterase. 3rd international meeting on esterases reacting with organophosphorous compounds. Dubrovnik, Croatia, 1998.
65. Amitai, G., Adani, R., Sod-Moria, G., Rabinovitz, I., Leader, H., Vince, A., Chefetz, B., Leibovitz-Persky, L., Friesem, D., Hadar, Y. Degradation of phosphorothiolates by oxidative enzymatic hydrolysis. Chemical and biological decontamination conference, St. Peterburg Fl, 1998.
66. Amitai G, Adani R, Sod-Moriah G, Leader H, et al. Oxidative biodegradation of phosphorothiolates by fungal laccase. Febs. Letters, 438 (3): 195-200, 1998.
67. Leader H, Vincze A, Manisterski B, et al. Characterization of O,O-diethylphosphoryl oximes as inhibitors of cholinesterases and substrates of phosphotriesterases. Biochem.Pharm. 58 (3): 503-515, 1999.
68. Luo CY, Saxena A, Ashani Y, Leader H, et al. Role of edrophonium in prevention of the re-inhibition of acetylcholinesterase by phosphorylated oxime. Chem.Bio.Inter., 120: 129-135, 1999.
69. Leader H, Wolfe AD, Chiang PK, et al. Pyridophens: Binary pyridostigmine-aprophen Prodrugs with differential inhibition of acetylcholinesterase, butyrylcholinesterase, and muscarinic receptors. J. Med. Chemistry, 45 (4): 902-910, 2002.
70. Ashani Y, Bhattacharjee AK, Leader H, et al. Inhibition of cholinesterases with cationic phosphonyl oximes highlights distinctive properties of the charged pyridine groups of quaternary oxime reactivators. Bio.Chem. Pharm., 66 (2): 191-202, 2003.
71. Luo CY, Leader H, Radic Z, et al. Two possible orientations of the HI-6 molecule in the reactivation of organophosphate-inhibited acetylcholinesterase, Bio. Chem. Pharm., 66 (3): 387- 392, 2003.
72. Waysbort D, Manisterski E, Leader H, et al., Laboratory setup for long-term monitoring of the volatilization of hazardous materials: Preliminary tests of O-ethyl-S-2-(N,N-diisopropylamino) ethyl methyl phosphonothiolate on asphalt, Environ. Sci. Technol., 38, 2217-2223, 2004.
73. Demar J.C., Clarkson E.D., Ratcliffe R.H., Campbell A.J., Thangavelu S.G., Herdman C.A., Leader H, Schulz S.M., Marek E, Medynets M.A., Ku T.C., Evans S.A., Khan F.A., Owens R.R., Nambiar M.P., Gordon R.K, “Pro-2-PAM therapy for central and peripheral cholinesterases”, Chem Biol Interact., 187, 191-198, 2010.
74. Ashani Y, Gupta R.D., Goldsmith M, Silman I, Sussman J.L., Tawfik D.S., Leader H., Stereo-specific synthesis of analogs of nerve agents and their utilization for selection and characterization of paraoxonase (PON1) catalytic scavengers, Chem. Biol. Interact., 187, 362-369, 2010.
75. Greenstein M, Ben Ishay R., Maoz B. M., Leader H., Vaskevich A., Rubinstein I., Rapid Formation of Coordination Multilayers Using Accelerated Self-Assembly Procedure (ASAP), Langmuir, 26, 7277–7284, 2010.
76. Gupta R. D., Goldsmith M., Ashani Y., Simo Y., Mullokandov G., Bar H., Ben-David M., Leader H., Margalit R., Silman I., Sussman J. L., Tawfik D. S., Directed evolution of hydrolases for prevention of G-type nerve agent intoxication, Nature Chemical Biology, 7, 120–125, 2011.
77. Chaikin Y., Leader H., Popovitz-Biro R., Vaskevich A., Rubinstein I., Versatile Scheme for the Step-by-Step Assembly of Nanoparticle Multilayers, Langmuir, 27, 1298–1307, 2011.

78.Khare, S. D.; Kipnis, Y.;Greisen, P., Jr.; Takeuchi, R.; Ashani, Y.; Goldsmith, M.; Song, Y.; Gallaher, J. L.; Silman, I.; Leader, H.; Sussman, J. L.; Stoddard, B. L.; Tawfik, D. S.; Baker, D., Computational redesign of a mononuclear zinc metalloenzyme for organophosphate hydrolysis, Nature Chemical Biology, 8, 294–300 2012.

79. Goldsmith, M.; Ashani, Y.; Simo, Y.; Ben-David, M; Leader, H.; Silman, I.; Sussman, J.; Tawfik, D., Evolved Stereoselective Hydrolases for Broad-Spectrum G-Type Nerve Agent Detoxification, Chemistry and Biology, 19 (4), 456 - 466, 2012.

Patents

1. Smejkal Ruthann M., Gordon Richard K., Doctor Bhupendra P., Chiang Peter K., Payne Charlotte S., Leader Haim, Padilla Felipe N., Carbaphens: aprophen analogs that are binary antidotes for organophosphate poisoning, Patent: US5026897(A).

2. Ashani Yacov, Bruckstein Rachel, Leader Haim, Raveh Lily, Spiegelstein Michael, Dioxaphosphorinanes, Patent: 4472320.

3. Tawfik Dan S., Gupta Rinkoo Devi, Goldsmith Moshe, Ashani Yaacov, Ben-David Moshe, Silman Israel, Sussman Joel L., Leader Haim, An isolated polypeptide comprising the amino acid sequence of serum paraoxonase (PON1) having catalytic efficiency of k cat /K M ≈106 M-1min-1 for a nerve-agent substrate, Patent: IL2010/000754.