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2.
J Org Chem ; 75(3): 702-15, 2010 Feb 05.
Article in English | MEDLINE | ID: mdl-20039638

ABSTRACT

Generally, the hetero-Diels-Alder reaction (Povarov reaction) of N-arylimine dienes are limited to reaction with activated, electron-rich alkenes. However, introduction of ring strain in the dienophile, as with moderately strained bicyclo[2.2.1]heptenes (norbornene), enables three-component Povarov reaction with in situ formed N-arylimines under Lewis acid catalyzed conditions (BF(3).OEt(2)). The reactions proceed efficiently with a diverse set of commercially available anilines and benzaldehydes, as well as a variety of substituted norbornenes. The corresponding tetrahydroquinolines are formed with high complexity in a multicomponent fashion and are obtained in good yield and high diastereoselectivity. In addition, more reactive ethyl glyoxylate derived imines were utilized to achieve faster, room temperature reactions with norbornene. In all cases, attack of the N-arylimine dienes occurred exclusively from the exo-face of the norbornene ring, but the relative stereochemistry of the substituent alpha to the tetrahydroquinoline nitrogen, as well as the regioselectivity of reaction, was shown to depend upon subtle substituent effects on the aniline precursors. In most cases, a preference for the formation of exo-exo diastereomeric adducts was observed, but for reactions of ortho- or meta-substituted anilines, the formation of exo-endo adducts was also observed. These observations may be rationalized by two competing mechanistic models, involving either a concerted asynchronous [4 + 2]-like mechanism or a stepwise mechanism.

3.
Bioorg Med Chem Lett ; 19(14): 3716-20, 2009 Jul 15.
Article in English | MEDLINE | ID: mdl-19497743

ABSTRACT

Irreversible chemical programming of monoclonal aldolase antibody (mAb) 38C2 has been accomplished with beta-lactam equipped mono- and bifunctional targeting modules, including a cyclic-RGD peptide linked to either the peptide (D-Lys(6))-LHRH or another cyclic RGD unit and a small-molecule integrin inhibitor SCS-873 conjugated to (D-Lys(6))LHRH. We also prepared monofunctional targeting modules containing either cyclic RGD or (D-Lys(6))-LHRH peptides. Binding of the chemically programmed antibodies to integrin receptors alpha(v)beta(3) and alpha(v)beta(5) and to the luteinizing hormone releasing hormone receptor were evaluated. The bifunctional and bivalent c-RGD/LHRH and SCS-783/LHRH, the monofunctional and tetravalent c-RGD/c-RGD, and the monofunctional bivalent c-RGD chemically programmed antibodies bound specifically to the isolated integrin receptor proteins as well as to integrins expressed on human melanoma M-21 cells. c-RGD/LHRH, SCS-783/LHRH, and LHRH chemically programmed antibodies bound specifically to the LHRH receptors expressed on human ovarian cancer cells. This approach provides an efficient, versatile, and economically viable route to high-valency therapeutic antibodies that target defined combinations of specific receptors. Additionally, this approach should be applicable to chemically programmed vaccines.


Subject(s)
Antibodies, Bispecific/chemistry , Antibodies, Monoclonal/chemistry , Antibodies, Bispecific/immunology , Antibodies, Bispecific/metabolism , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/metabolism , Biomimetic Materials/chemical synthesis , Biomimetic Materials/chemistry , Cell Line, Tumor , Fructose-Bisphosphate Aldolase/chemistry , Fructose-Bisphosphate Aldolase/immunology , Gonadotropin-Releasing Hormone/chemistry , Humans , Integrin alphaVbeta3/antagonists & inhibitors , Integrin alphaVbeta3/metabolism , Oligopeptides/chemistry , Receptors, LHRH/metabolism , Receptors, Vitronectin/antagonists & inhibitors , Receptors, Vitronectin/metabolism , beta-Lactamases/biosynthesis , beta-Lactamases/immunology
4.
Bioorg Med Chem Lett ; 19(5): 1421-4, 2009 Mar 01.
Article in English | MEDLINE | ID: mdl-19181522

ABSTRACT

Irreversible chemical programming of monoclonal aldolase antibody (mAb) 38C2 has been accomplished with beta-lactam-equipped targeting modules. A model study was first performed with beta-lactam conjugated to biotin. This conjugate efficiently and selectively modified the catalytic site lysine (LysH93) of mAb 38C2. We then conjugated a beta-lactam to a cyclic-RGD peptide to chemically program mAb 38C2 to target integrin receptors alpha(v)beta(3) and alpha(v)beta(5). The chemically programmed antibody bound specifically to the isolated integrin receptor proteins as well as the integrins expressed on human melanoma cells. This approach provides an efficient and versatile solution to irreversible chemical programming of aldolase antibodies.


Subject(s)
Antibodies, Catalytic/chemistry , Chemistry, Pharmaceutical/methods , Fructose-Bisphosphate Aldolase/chemical synthesis , beta-Lactams/chemical synthesis , Antibodies, Catalytic/metabolism , Cell Line, Tumor , Fructose-Bisphosphate Aldolase/metabolism , Humans , Immunoglobulin Fab Fragments/metabolism , beta-Lactams/metabolism
5.
J Comb Chem ; 9(4): 644-51, 2007.
Article in English | MEDLINE | ID: mdl-17580974

ABSTRACT

A method for the synthesis of polypeptides modified with a tetrazole ring at the N-terminus is described. Reaction of the N-terminal amino group of solid-supported peptides with arylisothiocyanates generates thiourea intermediates, which upon treatment with Mukaiyama's reagent (2-chloro-1-methylpyridinium iodide) generate electrophilic carbodiimide functionality. Trapping by the azide anion and electrocyclization of the intermediate imidoylazide generates an aryl-substituted 5-aminotetrazole at the N-terminus of the peptide. To prevent competitive cyclization of a neighboring amide N-H into the carbodiimide, there should not be a free N-H at the [X-1] position relative to the activated carbodiimide. Protection of the N-H group at this position or incorporation of a secondary amino acid is thus required for optimal tetrazole formation. Cleavage from the resin releases the hybrid molecules incorporating a 5-aminotetrazole ring conjugated onto a peptidic fragment.


Subject(s)
Azides/chemistry , Electrons , Heterocyclic Compounds/chemistry , Imides/chemistry , Peptides/chemical synthesis , Tetrazoles/chemistry , Cyclization , Databases, Protein , Heterocyclic Compounds/chemical synthesis , Hydantoins/chemistry , Molecular Structure , Peptides/chemistry , Thiourea/chemistry
6.
J Comb Chem ; 8(2): 237-46, 2006.
Article in English | MEDLINE | ID: mdl-16529519

ABSTRACT

A method for the heterocyclic modification of the N-terminus of a peptide is described. Reaction of the N-terminal amino group of solid-supported peptides with arylisothiocyanates generates a thiourea intermediate, as in the first step of Edman degradation. Treatment of the resin-supported peptide-thioureas with Mukaiyama's reagent (2-chloro-1-methylpyridinium iodide) generates an electrophilic carbodiimide functionality, which undergoes rapid intramolecular trapping by the adjacent amide group to give a 2-iminohydantoin ring at the N-terminus of the peptide. The dehydrothiolation step in the presence of Mukaiyama's reagent prevents Edman degradation from occurring, in essence leading to a "diversion" of the Edman degradation. Cleavage from the resin then releases the hybrid molecules incorporating a 2-iminohydantoin ring conjugated onto a peptidic fragment. A 400-member library of the iminohydantoin-peptide hybrids was synthesized using this approach, starting from a chlorotrityl resin-supported tripeptides.


Subject(s)
Heterocyclic Compounds , Hydantoins , Oligopeptides/chemical synthesis , Peptides/chemical synthesis , Imines , Models, Molecular , Molecular Structure , Oligopeptides/chemistry
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