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Several new amides and anilides of alpha-aziridinyl-beta-/p-chlorobenzoyl/-propionic acid were synthetized. The beta-/p-chlorobenzoyl/-acrylic acid 2 was used as the substrate. This compound was converted by reaction with appropriate amine into amides and anilides of beta-/p-chlorobenzoyl/-acrylic acid (3-10). These compounds react with ethylenoimine giving appropriate amides and anilides of alpha-aziridinyl-beta-/p-chlorobenzoyl/-propionic acid (11-18). When pharmacologically analyzed, they appeared to possess marked immunotropic activity. The derivatives in question modulated both humoral as well as cellular immune response, the effect being related to the type of substitutent in the amide group.
Several new aziridinyl derivatives of beta-/p-chlorobenzoyl/propionic acid were synthesized (3, 5, 7, 14-18). The gamma-/p-chlorophenyl/-dihydrofuran-2-one 2 and beta-/p-chlorobenzoyl/acrylic acid 4 were used as the substrates. Compound 2 reacts with ethylenimine yielding aziridinylamide of beta-/p-chlorobenzoyl/-propionic acid 3. The sodium salt of acid 4 and methyl ester 6 were converted by reactions with ethylenimine into appropriate alpha-aziridinyl derivatives 5 and 7. The acid 4 in the reaction with phosphorus pentachloride gives the acid chloride 8 which is transformed under the influence of appropriate amines into corresponding amides 9-13. These amides react with ethylenimine giving the appropriate alpha-aziridinyl derivatives of beta-/p-chlorobenzoyl/-propionic acid 14-18. Pharmacological analysis revealed that the compounds studied possessed immunotropic activity; they modulate both humoral as well as cellular immune response. Their effect has been shown to be related to chemical structure and to substituents of the carboxyl group in particular.
A new class of compounds, the 2-cyanaziridines, has immune-modulating properties. This immune-modulation was proved by the influence on the delayed type hypersensitivity reaction, the increase of the lymphocyte transformation by T-cell-specific mitogens ConA and PHA, the increase of phagocytosis of macrophages, the increase of resistance against bacterial, fungal and virus infections and by the influence on various transplantation tumors in mice and rats.
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Expression of genes encoding prodrug-activating enzymes can increase the susceptibility of tumor cells to prodrugs, and may ultimately achieve a better therapeutic index than conventional chemotherapy. CB1954 is a weak, monofunctional alkylating agent which can be activated by Escherichia coli nitroreductase to a potent dysfunctional alkylating agent which crosslinks DNA. We have inserted the nitroreductase gene into an LNCX-based retroviral vector, to allow efficient gene transfer and expression in colorectal (LS174T) and pancreatic (SUIT2, BxPC3, and AsPC1) cancer cell lines. A clone of LS174T cells expressing nitroreductase showed > 50-fold increased sensitivity to CB1954, and nitroreductase-expressing clones of pancreatic tumor lines were up to approximately 500-fold (SUIT2) more sensitive than parental cells. Concentrations of CB1954 minimally toxic to nontransduced cells achieved 100% cell death in a 50:50 mix of parental cells with SUIT2 cells expressing nitroreductase; and marked "bystander" cell killing was seen with just 10% of cells expressing nitroreductase. Significant bystander cell killing was dependent on a high cell density. In conjunction with regional delivery of vectors and tumor selectivity of cell entry and/or gene expression, nitroreductase and CB1954 may be an attractive combination for prodrug-activating enzyme gene therapy of colorectal and pancreatic cancer.
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