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2.
Int Immunopharmacol ; 1(3): 539-50, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11367537

ABSTRACT

beta-Glucans are polysaccharides that act as nonspecific immune system stimulants. However, many beta-Glucans are sparingly soluble in water. This work describes an oxidative procedure, which solubilizes the beta-Glucan from Saccharomyces cerevisiae and maintains its immunostimulatory properties. Furthermore, the carboxylates at the site of oxidation allow for the conjugation of small molecule immunostimulants. Both the parent oxidized beta-glucan and its conjugates with O-beta-alanyl-5-[6-(N,N'-dimethylamino)purin-9-yl]pentanol stimulate cytotoxic T-lymphocytes (CTLs), B cells and macrophages. In addition, they both stimulate natural killer (NK) cells, a property which the small molecule purine does not possess.


Subject(s)
Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/pharmacology , Glucans/chemistry , Glucans/pharmacology , Adjuvants, Immunologic/isolation & purification , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , Carbohydrate Sequence , Female , Glucans/isolation & purification , Humans , In Vitro Techniques , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Macrophages/drug effects , Macrophages/immunology , Mice , Mice, Inbred C57BL , Molecular Sequence Data , Oxidation-Reduction , Saccharomyces cerevisiae/chemistry , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology
3.
Bioorg Med Chem Lett ; 10(19): 2223-6, 2000 Oct 02.
Article in English | MEDLINE | ID: mdl-11012034

ABSTRACT

Two series of 1,3-dioxolanes and 1,3-oxathiolane nucleosides containing N-9-oxypurine were synthesized as potential antiviral agents. These compounds were prepared by reacting the sugar moieties with iodo- or bromotrimethylsilane, followed by treatment with a mixture of sodium hydride and the desired N-hydroxy purine base. The preparation of these N-hydroxybases was also described. No significant antiviral activity was observed against HIV, HBV, HSV-1, HSV-2, or HCMV.


Subject(s)
Anti-HIV Agents/chemical synthesis , Antiviral Agents/chemical synthesis , Dioxolanes/chemical synthesis , Dioxolanes/pharmacology , Nucleosides/chemical synthesis , Nucleosides/pharmacology , Purine Nucleosides/chemical synthesis , Purine Nucleosides/pharmacology , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Line , Cytomegalovirus/drug effects , Dioxolanes/chemistry , Hepatitis B virus/drug effects , Humans , Molecular Structure , Nucleosides/chemistry , Purine Nucleosides/chemistry , Simplexvirus/drug effects
4.
Int J Immunopharmacol ; 22(9): 659-71, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10884587

ABSTRACT

N,N-dimethylaminopurine pentoxycarbonyl D-arginine (BCH-1393) is a novel low molecular weight synthetic immunomodulator that has been shown to significantly stimulate cytotoxic T-lymphocyte responses both in vitro and in vivo (Zacharie B, Gagnon L, Attardo G, Connolly TP, St-Denis Y, Penney CL. Synthesis and activity of 6-substituted purine linker amine immunostimulants. J. Med. Chem. 1997;40:2883-94). Prompted by this evidence, we extended evaluation of BCH-1393 for anticancer activity in syngeneic mouse experimental tumor models. Consistent with previous findings, in vitro assessment of BCH-1393 activity demonstrated a significant increase in the CTL responses in the range of 10(-9)-10(-5) M. Treatment of mice with four consecutive daily intraperitoneal injections at 25 and 50 mg/kg resulted in a significant increase of the relative percentage of blood CD4+, CD8+, NK and monocyte subsets without any evidence of toxicity. In vivo anti-tumor activity of BCH-1393 was evaluated, either alone or in combination with subtherapeutic doses of cyclophosphamide (Cy), against weakly immunogenic mouse breast carcinoma DA-3 and strongly immunogenic colon adenocarcinoma MC38. Daily intraperitoneal injection of BCH-1393 at 50 mg/kg alone was well tolerated but produced a relatively weak anti-tumor effect in both tumor models. However, a significant inhibition of tumor outgrowth and suppression of established tumor growth was observed when BCH-1393 was administered in combination with subtherapeutic doses of Cy. Combination treatment of 50 mg/kg BCH-1393 with 100 mg/kg Cy (given as single intravenous bolus injection) starting 2 days prior to DA-3 tumor cell inoculation prevented tumor outgrowth in 70-80% of treated mice. In the remaining 20-30% of mice that had developed tumors, a nearly complete (90%) tumor growth inhibition was observed at days 22-24 post tumor implant. In the MC38 tumor model, combination treatment of established tumors with BCH-1393 and Cy (CTX) at 50 mg/kg resulted in a significant delay in tumor growth compared to CTX treatment alone. The observed concomitant anti-tumor activity of BCH-1393 with cyclophosphamide warrants further investigation of this immunomodulator as an adjunctive treatment of cancer.


Subject(s)
Arginine/analogs & derivatives , Arginine/therapeutic use , Colonic Neoplasms/drug therapy , Cyclophosphamide/therapeutic use , Mammary Neoplasms, Experimental/drug therapy , Purines/therapeutic use , T-Lymphocytes, Cytotoxic/immunology , Adjuvants, Immunologic/pharmacology , Adjuvants, Immunologic/therapeutic use , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Arginine/pharmacology , CD4-Positive T-Lymphocytes/drug effects , Colonic Neoplasms/immunology , Cyclophosphamide/pharmacology , Cytotoxicity Tests, Immunologic , Drug Evaluation, Preclinical , Drug Synergism , Female , Immunophenotyping , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/therapeutic use , Killer Cells, Natural/drug effects , Mammary Neoplasms, Experimental/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Monocytes/drug effects , Purines/pharmacology , T-Lymphocytes, Cytotoxic/drug effects , Time Factors , Tumor Cells, Cultured
5.
Vaccine ; 18(18): 1886-92, 2000 Mar 17.
Article in English | MEDLINE | ID: mdl-10699337

ABSTRACT

The tetrapeptide I (D-lysine-L-asparaginyl-L-prolyl-L-tyrosine or D-LysAsnProTyr), and analogue sequences, were synthesized and evaluated for the ability to stimulate immune cell subsets. These sequences were selected based on their perceived ability to readily adopt a beta-turn structure. In vitro immunological assays revealed a robust stimulation of mitogen activated B-cell proliferation and a modest to significant stimulation of cytotoxic T lymphocytes (CTLs). Further, this in vitro stimulation of B-cells was accompanied by an in vivo expansion of B-cells in C57BL/6 mice, as demonstrated by immunophenotyping experiments. Interestingly, a conformational analysis of the low energy conformers of I and the endogenous B-cell stimulant bursin (LysHisGlyNH2) shows that these molecules can be superimposed. However, I displayed significantly enhanced physiological stability. For a number of reasons, I may be a particularly useful vaccine adjuvant.


Subject(s)
B-Lymphocyte Subsets/immunology , Lymphocyte Activation/immunology , Molecular Mimicry , Oligopeptides/chemistry , Oligopeptides/immunology , Animals , Asparagine/immunology , Cells, Cultured , Female , Half-Life , Lysine/immunology , Mice , Mice, Inbred C57BL , Oligopeptides/pharmacology , Proline/immunology , Spleen , Tyrosine/immunology
6.
J Med Chem ; 42(11): 2046-52, 1999 Jun 03.
Article in English | MEDLINE | ID: mdl-10354413

ABSTRACT

Imreg (Tyr1-Gly2-Gly3) is a well-known immunostimulant. However, it possesses a short half-life. Stabilized analogues of Imreg were prepared by a regioselective insertion in which peptide bonds at position 1,2 or 2,3 were replaced by thioamide linkages. This was achieved by using new thioacylating agents based on thioacyl-fluoro-N-benzimidazolone. The synthesis and properties of these reagents are described herein. This peptide modification enhanced significantly the half-life of the thioanalogues relative to Imreg in blood. The thioanalogues and Imreg were tested in vitro in T and B cell proliferation assays and for their ability to stimulate cytotoxic T-lymphocytes (CTLs). Only thiotyrosyl glycyl glycine 11 displayed some activity as evidenced by a weak stimulation of CTLs. On the basis of this activity and the increased stability, an in vivo immunological evaluation was undertaken. Immunophenotyping of 11 revealed a significant increase in activated CTL and NK cell populations in the spleen. This expansion was also accompanied by a significant stimulation of NK cells and the B cell proliferative response. Thioanalogues of Imreg were generally nontoxic, as exemplified by 11. The latter is a promising immunostimulant which may be targeted for cancer and viral infections, where CTLs and NK cells play an important role, or as a vaccine adjuvant where stimulation of antibody-producing B cells is important.


Subject(s)
Adjuvants, Immunologic/chemical synthesis , Oligopeptides/chemistry , Oligopeptides/chemical synthesis , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/pharmacology , Animals , Cell Division/drug effects , Cells, Cultured , Drug Stability , Endopeptidases/chemistry , Female , Immunophenotyping , Kidney/enzymology , Kidney/ultrastructure , Killer Cells, Natural/drug effects , Mice , Mice, Inbred C57BL , Microvilli/enzymology , Oligopeptides/pharmacology , Rats , Spleen/cytology , Spleen/drug effects , Spleen/immunology
7.
J Med Chem ; 41(11): 1909-26, 1998 May 21.
Article in English | MEDLINE | ID: mdl-9599240

ABSTRACT

Water soluble analogues of the lipophilic immunostimulant, octadecyl D-alanyl-L-glutamine, BCH-527, were synthesized and evaluated for the ability to stimulate natural killer (NK) cells. One of these compounds in which the octadecyl chain of BCH-527 was replaced with a shorter chain alcohol, 6-(D-alanyl-L-glutaminylamino)hexan-1-ol, 9, displayed an in vitro stimulation of NK cells comparable to that of interleukin 2 (IL 2). However, when the hydroxyl of 9 was linked to L-fucose to yield 1-beta-[6-(D-alanyl-L-glutaminylamino)hex-1-yl]-L- fucopyranose (BCH-2537, 1), the observed stimulation of NK cells was greater than that observed with IL 2. Further evaluation of these compounds revealed that the improved in vitro activity of BCH-2537 was more pronounced in vivo. That is, while both compounds significantly increased splenic NK cells, only BCH-2537 significantly increased the activity of these cells in vivo. In terms of a structure-activity relationship, NK cell activity was sensitive to minor structural modifications. It was influenced by conservative substitutions within the dipeptide, the length of the hydrocarbon chain, and the functionality at the end of the chain. No other compound enhanced NK cell activity to the extent exhibited by BCH-2537, although a few were equipotent to 9.


Subject(s)
Adjuvants, Immunologic , Dipeptides , Fucose/analogs & derivatives , Hexanols , Killer Cells, Natural/drug effects , Lymphocyte Activation/drug effects , Adjuvants, Immunologic/chemical synthesis , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/pharmacology , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , Dipeptides/chemical synthesis , Dipeptides/chemistry , Dipeptides/pharmacology , Female , Fucose/chemical synthesis , Fucose/chemistry , Fucose/pharmacology , Hexanols/chemical synthesis , Hexanols/chemistry , Hexanols/pharmacology , Immunophenotyping , Killer Cells, Natural/immunology , Lymphocyte Culture Test, Mixed , Mice , Mice, Inbred C57BL , Mitogens/chemical synthesis , Mitogens/chemistry , Mitogens/pharmacology , Phagocytosis/drug effects , Phagocytosis/immunology , Respiratory Burst/drug effects , Respiratory Burst/immunology , Spleen/cytology , Spleen/drug effects , Spleen/immunology , Structure-Activity Relationship , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology
8.
J Med Chem ; 40(18): 2883-94, 1997 Aug 29.
Article in English | MEDLINE | ID: mdl-9288170

ABSTRACT

A series of 6-substituted purinyl alkoxycarbonyl amino acids were synthesized and evaluated for their ability to stimulate cytotoxic T lymphocytes (CTLs) and the mixed lymphocyte reaction (MLR). A few of these compounds, in particular [[5-[6-(N,N-dimethylamino)purin-9-yl]pentoxy]-carbonyl]D-arginine (BCH-1393, 4a), displayed an in vitro stimulation of CTLs comparable to interleukin 2 (IL 2). BCH-1393 increased the CTL response between 10(-9) M and 10(-5) M. Further, this potent in vitro activity was reflected as a significant increase in CTL cell number in vivo. However, immunophenotyping of some of the other equipotent compounds did not reveal a parallel relative increase in CTLs in vivo. It was difficult to formulate a rigorous structure-activity relationship based on in vitro CTL activity. Nevertheless, the activity was dependent upon the nature of the 6-substituent on the purine, the type and stereochemistry of the amino acid, and the distance and spatial freedom between the purine and amino acid as defined by the length and rigidity of the linker. These compounds were generally nontoxic, as exemplified by BCH-1393. BCH-1393 is a promising immunostimulant which may be targeted for those disease states which require an increased CTL or TH1 type response.


Subject(s)
Adjuvants, Immunologic/chemical synthesis , Amino Acids , Arginine/analogs & derivatives , Lymphocyte Activation/drug effects , Purines/chemical synthesis , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Cytotoxic/drug effects , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/pharmacology , Animals , Arginine/chemical synthesis , Arginine/chemistry , Arginine/pharmacology , Female , Immunophenotyping , Interleukin-2/biosynthesis , Lymphocyte Culture Test, Mixed , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Mice, Inbred C57BL , Molecular Structure , Purines/chemistry , Purines/pharmacology , Spleen/immunology , Structure-Activity Relationship , T-Lymphocyte Subsets/drug effects , T-Lymphocytes, Cytotoxic/immunology
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