ABSTRACT
A series of A-ring pyrrole derivatives of duocarmycin bearing beta-(5',6',7'-trimethoxy-2'-indolyl)acryloyl group were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. New Seg-B analogues bearing beta-(5',6',7'-trimethoxy-2'-indolyl)acryloyl group containing double bond as spacer had lower peripheral blood toxicity than the derivatives bearing 5',6',7'-trimethoxyindole-2'-carboxyl group in Seg-B of the natural type. Moreover, most of them exhibited potent antitumor activity against in vivo murine tumor models.
Subject(s)
Antibiotics, Antineoplastic/chemical synthesis , Antibiotics, Antineoplastic/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Pyrrolidinones/chemistry , Pyrrolidinones/pharmacology , Animals , Antibiotics, Antineoplastic/toxicity , Cell Division/drug effects , Duocarmycins , HeLa Cells , Humans , Inhibitory Concentration 50 , Leukocyte Count , Male , Mice , Neoplasms, Experimental/drug therapy , Platelet Count , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/pharmacology , Pyrrolidinones/chemical synthesis , Time Factors , Transplantation, Heterologous , Tumor Cells, CulturedABSTRACT
A series of the C7-substituted A-ring pyrrole derivatives of duocarmycin were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. All of the C7-substituted A-ring pyrrole compounds decreased potency in vitro and in vivo. However, some showed strong antitumor activity with T/C values less than 0.3. Among them, the 7-formyl compound 5d showed remarkable potent in vivo antitumor activity and low peripheral blood toxicity, which were equal to 2c.
Subject(s)
Antineoplastic Agents/chemistry , Pyrroles/chemistry , Pyrrolidinones/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , HeLa Cells , Humans , Magnetic Resonance Spectroscopy , Mice , Pyrrolidinones/chemical synthesis , Pyrrolidinones/pharmacology , Spectrometry, Mass, Fast Atom BombardmentABSTRACT
A series of the 8-O-substituted A-ring pyrrole derivatives of duocarmycin bearing the simplified DNA-binding moieties such as cinnamoyl or heteroarylacryloyl groups were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. In addition, the stability of the 8-O-substituted analogues in aqueous solution and the conversion to their active form (cyclopropane compound) from the 8-O-substituted analogues in mice or human serum were examined. The 8-O-substituted A-ring pyrrole derivatives bearing the simplified DNA-binding moieties showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the 8-O-substituted A-ring pyrrole derivatives having the trimethoxyindole skeleton in segment-B (Seg-B), which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates and 4'-methoxy-beta-heteroarylacrylates. Moreover, among 8-O-substituted analogues, several compounds can be chemically or enzymatically converted to their active form in human serum. This result indicated that new 8-O-substituted derivatives were different prodrugs from KW-2189 and 8-O-substituted analogues being the same type of prodrug as KW-2189.
Subject(s)
Antibiotics, Antineoplastic/chemistry , Pyrroles/chemistry , Pyrrolidinones/chemistry , Animals , Antibiotics, Antineoplastic/adverse effects , Antibiotics, Antineoplastic/chemical synthesis , Antibiotics, Antineoplastic/pharmacology , Blood Cell Count/drug effects , DNA/drug effects , Drug Screening Assays, Antitumor , Humans , Magnetic Resonance Spectroscopy , Male , Mice , Pyrrolidinones/adverse effects , Pyrrolidinones/chemical synthesis , Pyrrolidinones/pharmacology , Spectrometry, Mass, Fast Atom Bombardment , Tumor Cells, CulturedABSTRACT
A series of A-ring pyrrole compounds of duocarmycin bearing 5-membered heteroarylacryloyl groups (thienylacryloyl and pyrrolylacryloyl) and heteroarylcarbonyl groups were synthesized and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. Most of the thienylacrylates displayed in vitro anticellular activity equivalent to 4'-methoxycinnamates. Among the 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of methoxy-thienylacrylates, compound 11b, having 4'-methoxy-2'-thienylacryloyl as segment-B (Seg-B), showed remarkably potent antitumor activity and low peripheral blood toxicity in vivo, which were equal to those of 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates, compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in Seg-B. On the other hand, the 2'-pyrrolylacrylates having a double bond as spacer showed 10(2)- to 10(3)-fold stronger anticellular activity than 2'-pyrrolecarboxylates (IC50 < 0.3 nM, 72 h-exposure). The 8-O-acetate and 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 2'-pyrrolylacrylates exhibited an antitumor effect at a lower dose compared with the 8-O-[(N-methylpiperazinyl] derivatives of 4'-methoxycinnamate (1j). Moreover, it was expected that the antitumor activity would be increased by the strength of the extra hydrogen bond formed between the nitrogen of the pyrrole amido group and DNA, owing to the increase of the number of N-methyl-2'-pyrrolecarboxamide units. However, 2'-pyrrolylacrylates having three N-methyl-2'-pyrrolecarboxamide units showed nearly equal antitumor activity to 2'-pyrrolylacrylates having only one N-methyl-2'-pyrrolecarboxamide unit.
Subject(s)
Antineoplastic Agents/chemical synthesis , Indoles , Pyrroles/chemistry , Pyrroles/chemical synthesis , Acrylates/chemistry , Acrylates/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Blood Cells/drug effects , Combinatorial Chemistry Techniques , DNA/drug effects , DNA/metabolism , Duocarmycins , HeLa Cells , Humans , Mice , Models, Chemical , Pyrroles/pharmacology , Pyrrolidinones/chemistry , Sarcoma 180 , Structure-Activity RelationshipABSTRACT
A series of 3-substituted A-ring pyrrole compounds of duocarmycin were synthesized and evaluated for in vitro anticellular activity against HeLa S(3) cells and in vivo antitumor activity against murine sarcoma 180 in mice. These compounds were evaluated on the peripheral blood toxicity and delayed lethal toxicity. Further, to expand our investigation of their peripheral blood toxicity, the toxicity to bone marrow cells (CFU-GM, CFU-Meg) was investigated. Among 3-substituted A-ring pyrrole compounds of duocarmycin bearing a 5',6',7'-trimethoxy-2'-indolecarboxyl group as segment-B (Seg-B), several analogues showed remarkably potent antitumor activity with low peripheral blood toxicity. The 3-formyl compound 12h, one of such analogues, showed stronger antitumor activity with lower toxicity to bone marrow cells compared to DU-86 (2a), an active metabolite of KW-2189 (2b). However, compound 12h caused delayed death. On the other hand, the 3-bromo compound 15f, one of the 3-substituted A-ring pyrrole derivatives bearing a 4'-methoxycinnamoyl group as Seg-B, showed the most potent antitumor activity among the 4'-methoxycinnamate analogues with low toxicity to bone marrow cells. Furthermore, compound 15f did not cause delayed death similarly to 2d. These results would indicate the importance of the C-3 substituents of A-ring pyrrole duocarmycin derivatives for exhibiting antitumor activity and decreasing toxicity.
Subject(s)
Antineoplastic Agents/chemical synthesis , Indoles/chemical synthesis , Pyrrolidinones/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/toxicity , Bone Marrow Cells/drug effects , Colony-Forming Units Assay , Drug Screening Assays, Antitumor , Humans , Indoles/chemistry , Indoles/pharmacology , Indoles/toxicity , Inhibitory Concentration 50 , Leukocyte Count/drug effects , Male , Mice , Neoplasm Transplantation , Platelet Count/drug effects , Pyrrolidinones/chemistry , Pyrrolidinones/pharmacology , Pyrrolidinones/toxicity , Sarcoma 180/drug therapy , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A series of A-ring pyrrole compounds of duocarmycin bearing 4'-methoxy-beta-heteroarylacryloyl groups were synthesized and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. Most of the 4'-methoxy-beta-heteroarylacrylates displayed in vitro anticellular activity equivalent to that of 4'-methoxycinnamates. Among the 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxy-beta-heteroarylacrylates, compound 15b having a (4-methoxy-3,5-pyrimidinyl)acryloyl as segment-B (Seg-B) showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in Seg-B, which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates. Moreover, these 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxy-beta-heteroarylacrylates had high aqueous solubility.
Subject(s)
Indoles/chemical synthesis , Pyrroles/chemical synthesis , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Animals , Blood Platelets/cytology , Blood Platelets/drug effects , Drug Screening Assays, Antitumor , HeLa Cells , Humans , In Vitro Techniques , Indoles/chemistry , Indoles/pharmacology , Inhibitory Concentration 50 , Male , Mice , Mice, Nude , Neoplasm Transplantation , Pyrroles/chemistry , Pyrroles/pharmacology , Sarcoma 180/drug therapy , Sarcoma 180/pathology , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
A series of N-cinnamates of the A-ring pyrrole compound of duocarmycin were synthesized and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. The 4'-methoxy- and 4'-BocNH-cinnamates exhibited strong in vitro anticellular activity among the synthesized compounds. The ortho substitution of the 4'-methoxycinnamate did not affect the anticellular activity and contributed to an enhancement of water solubility. Most of the 8-O-(N,N-dialkylcarbamoyl) derivatives of the 4'-methoxycinnamate displayed remarkably superior in vivo antitumor activity to duocarmycin A or B2. Moreover, it is noteworthy that these 8-O-(N,N-dialkylcarbamoyl) derivatives exhibited significant antitumor activity at wider range of doses as compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in segment B.
