RESUMEN
1,4-Dihydroxy-5,8-bis(((2[(2-hydroxyethyl)amino]ethyl)amino))-9,-10-anthracenedione dihydrochloride (CL 232315; NSC 301739D), a representative of a new chemical class of compounds with antineoplastic properties, has been evaluated for antitumor activity in experimental mouse tumor systems. The compound produced significant increases in life span (ILS) and long-term survivors when tested against the P388 and L1210 leukemias as well as the solid neoplasms, B16 melanoma and Colon Tumor 26. The optimal treatment regimens resulted in a 173 to greater than 200% ILS with 20 to 80% 60-day survivors in mice with P388 leukemia, A 205% ILS with 55% 60-day survivors in mice with L1210 leukemia, and an ILS of greater than 300% with 80% 90-day survivors in mice with B16 melanoma. In contrast to Adriamycin, CL 232315 was active against the i.v. implanted L1210 leukemia and demonstrated moderate activity against P388/Adria, a subline of P388 resistant to Adriamycin. The compound was ineffective when tested against the Lewis lung carcinoma and the Ridgway osteogenic sarcoma. CL 232315 was active i.p., s.c., and i.v., but p.o. activity was not demonstrated. Schedule dependency was not observed when the compound was administered once daily for nine days, once every four days, or as a single dose.
Asunto(s)
Antracenos/farmacología , Antineoplásicos , Neoplasias Experimentales/tratamiento farmacológico , Animales , Antracenos/administración & dosificación , Neoplasias del Colon/tratamiento farmacológico , Inyecciones , Leucemia Experimental/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Melanoma/tratamiento farmacológico , Ratones , Ratones EndogámicosRESUMEN
9,10-Anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] dihydrochloride (CL 216942; bisantrene hydrochloride; NSC 337766), a member of a new chemical class of compounds with antineoplastic properties, has been evaluated for antitumor activity in experimental murine tumor systems. The compound produced significant increases in life span (LS) and long-term survivors among mice bearing transplantable leukemias and solid tumors. Optimal treatment regimens resulted in an ILS of greater than 173 and 151% in mice with P388 and L1210 leukemia, respectively, an ILS of greater than 85% in mice with Lieberman plasma cell tumor, and an ILS of greater than 200, 150, and 63%, respectively, in mice with B16 melanoma, colon tumor 26, and Ridgway osteogenic sarcoma. An adriamycin-resistant subline of P388 leukemia showed complete cross-resistance to CL of 216942. The compound was active when administered by the i.p., i.v., and s.c. routes, but p.o. activity was not observed. Significant schedule dependency was not observed when the drug was administered once daily for 9 days, once every 4 days, or as a single dose, but single doses typically produced the best effects. CL 216942 was a potent inhibitor of DNA and RNA synthesis in L5178Y lymphoma cells cultured in vitro, and preliminary studies indicated the drug was a DNA-intercalating agent. The drug was cytotoxic for rapidly proliferating and nonproliferating (G0) human colon carcinoma WiDR cells in vitro.U
Asunto(s)
Antracenos/uso terapéutico , Antineoplásicos , Leucemia Experimental/tratamiento farmacológico , Neoplasias Experimentales/tratamiento farmacológico , Animales , Antracenos/administración & dosificación , Doxorrubicina/uso terapéutico , Esquema de Medicación , Evaluación Preclínica de Medicamentos , Femenino , Fluorouracilo/uso terapéutico , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Inyecciones Subcutáneas , Leucemia L1210/tratamiento farmacológico , Leucemia P388/tratamiento farmacológico , Leucemia P388/patología , Masculino , Melanoma/tratamiento farmacológico , Melanoma/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Plasmacitoma/tratamiento farmacológico , Plasmacitoma/patologíaRESUMEN
Two polar metabolites of mitoxantrone, a clinically active antitumor agent, have been isolated and purified from the urine of patients by sequential absorption on glass wool and C18-Sep-Pak cartridges followed by preparative high-performance liquid chromatography. Negative ion chemical ionization mass spectrometry indicated that the two metabolites are the di- and mono-carboxylic acids resulting from oxidation of the terminal hydroxyl groups of the side chain(s). Mass spectral comparison of the urinary metabolites with synthetic compounds confirmed the identification.
Asunto(s)
Antraquinonas/orina , Antraquinonas/metabolismo , Cromatografía Líquida de Alta Presión , Humanos , Espectrometría de Masas , MitoxantronaRESUMEN
The preparation and antitubercular properties of a series of 2,8-bis(alkylaminomethyl)phenazines are described. These compounds all inhibited the growth of Mycobacterium smegmatis ATCC 607 in vitro. 2,8-Bis(dibutylaminomethyl)phenazine (5c) was also active against a lethal Mycobacterium tuberculosis H37Rv infection in mice.
Asunto(s)
Antituberculosos/síntesis química , Fenazinas/síntesis química , Animales , Ratones , Pruebas de Sensibilidad Microbiana , Mycobacterium/efectos de los fármacos , Fenazinas/farmacologíaRESUMEN
The selective phosphorylation of bisantrene (1) affords bis(phosphonoguanidinic acid) 6, a prodrug with enhanced aqueous solubility (as sodium salt 7) at physiological pH. Unlike 1, in a rat tail vein model, no precipitation was observed when bis(phosphonoguanidinic acid) 6 was injected. While in rats 6 hydrolyzed to monophosphonoguanidinic acid 9 with a half-life of ca. 12 min., complete hydrolysis to bisantrene required several hours. The corresponding monophosphonoguanidinic acid 9 was synthesized from bisantrene and also showed good solubility and antitumor activity. While the antitumor activities of 6 in mice were comparable to bisantrene against B-16 melanoma and P-388 and L-1210 leukemias, it was inactive in vitro vs several tumor cell types. Thus, its activity in vivo resulted from its ability to serve as a prodrug for bisantrene.
Asunto(s)
Antibióticos Antineoplásicos/síntesis química , Profármacos/síntesis química , Animales , Antracenos/síntesis química , Antracenos/farmacología , Leucemia P388/tratamiento farmacológico , Melanoma Experimental/tratamiento farmacológico , Ratones , Ratas , Ratas Sprague-DawleyRESUMEN
The condensation of alkylenediamines with quinizarin or with 2,3-dihydro-1,4,5,8-tetrahydroxy-9,10-anthracenedione, followed by oxidation, gave 1,4-bis[aminoalkyl)amino]-9,10-anthracenediones. Some of these compounds and their 2,3-dihydro derivatives were markedly active against both leukemias and solid tumors in mice. Activity was maximal with 5,8-dihydroxylation and 1,4-bis[(2-aminoethyl)amino] substitution, in which the terminal nitrogen atoms were either unsubstituted (compound 50) or carried 2-hydroxyethyl groups (compound 40), indicating the importance of hydrophilicity. Against B-16 melanoma, 50 gave greater than 433% increase in median life span (ILS) with 7/10 80-day survivors. Against P-388 leukemia, 40 gave greater than 500% ILS with 4/5.60-day survivors; its efficacy and therapeutic index equaled or surpassed those of adriamycin, cyclophosphamide, daunorubicin, methotrexate, or 5-fluorouracil. Against L-1210 leukemia, B-16 melanoma, and colon tumor 26, 40 was generally as effective or more effective than adriamycin and is now undergoing preclinical toxicological evaluation.
Asunto(s)
Antracenos/síntesis química , Antineoplásicos/síntesis química , Animales , Antracenos/farmacología , Antracenos/uso terapéutico , Antineoplásicos/uso terapéutico , Leucemia Experimental/tratamiento farmacológico , Ratones , Neoplasias Experimentales/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
A series of bisamidines of 2,6-diaminoanthraquinone was synthesized and tested against cecal and hepatic forms of Entamoeba histolytica infections in rats and hamsters, respectively. A number of compounds were found to have good activity against infections in both species.
Asunto(s)
Amebiasis/tratamiento farmacológico , Antraquinonas/uso terapéutico , Entamebiasis/tratamiento farmacológico , Amebicidas/síntesis química , Amidinas/síntesis química , Amidinas/uso terapéutico , Animales , Antraquinonas/síntesis química , Cricetinae , Disentería Amebiana/tratamiento farmacológico , Entamoeba histolytica , Femenino , Absceso Hepático Amebiano/tratamiento farmacológico , RatasRESUMEN
A series of 3,6-bis(aminoalkoxy)acridines (2) was prepared and shown to have a protective antiviral effect against an interferon-sensitive virus (Columbia SK) and to partially restore an antibody response to a T-cell-dependent antigen in leukemic immunosuppressed mice. The presence of circulating interferon and the stimulation of natural killer cell activity in mice was observed for 21.
Asunto(s)
Acridinas/síntesis química , Formación de Anticuerpos/efectos de los fármacos , Acridinas/farmacología , Animales , Antivirales/síntesis química , Antivirales/farmacología , Terapia de Inmunosupresión , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , RatonesRESUMEN
9,10-Anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] (bisantrene, VI-1) showed anticancer activity in mice vs. both leukemias and solid tumors. Increases in life span vs. the following neoplasms were: P-388 leukemia, 137%; B-16 melanoma, 122%; Lieberman plasma cell tumor, greater than 85%; colon tumor 26, 150%; Ridgway osteogenic sarcoma, 85%. There were significant numbers of long-term survivors. Both DNA and RNA synthesis were strongly inhibited. The drug was resistant to biodegradation and was bound strongly to tissues; in monkeys the half-life for disappearance from serum was 6 days. Related hydrazones were synthesized, and structure-activity relationships are discussed. Two routes to ring-substituted anthracene-9,10-dicarboxaldehyde intermediates were developed.
Asunto(s)
Antracenos/síntesis química , Antineoplásicos/síntesis química , Animales , Antracenos/metabolismo , Antracenos/farmacología , Antineoplásicos/metabolismo , Fenómenos Químicos , Química , Perros , Semivida , Haplorrinos , Humanos , Ratones , Relación Estructura-ActividadRESUMEN
Flexibility of intercalation site geometries within a B-DNA helix was investigated in the twist-shift plane using energy minimization methods. The parameters optimized included sugar conformation, the glycosidic angles and phosphodiester torsion angles. Our calculations show several regions of energetically favorable intercalation geometries in the twist-shift plane. Modeling studies using interactive computer graphics and electrostatic potential surface compatibility provided initial hypotheses for the structures of the drug-DNA complexes. These hypotheses were supported and extended by energy minimizations of these complexes. Binding positions, conformational features and relative minimum binding energies of two anticancer drugs, mitoxantrone and bisantrene, were computed for intercalation complexes with DNA in the theoretically defined intercalation sites. Mitoxantrone intercalates DNA from the minor groove and the side chain OH or NH groups are involved in hydrogen bonds with the main chain phosphate groups of DNA, thereby cross-linking the complementary strands. The hydroxyl groups of mitoxantrone can also participate in hydrogen bonding with phosphate oxygens of another chain, thereby cross-linking DNA helices. Bisantrene intercalates DNA favorably from the major groove and the NH group of the dihydroimidazole ring can participate in hydrogen bonding with the phosphate oxygens of the backbone. These models are consistent with the physicochemical and electron microscopic studies of the interaction of mitoxantrone and bisantrene with DNA. Our results are now being used to guide the design of novel anticancer drugs that should interact with DNA in a manner similar to that proposed for our representative drugs.
Asunto(s)
Antineoplásicos/síntesis química , Química Farmacéutica/métodos , Antracenos/metabolismo , Antraquinonas/metabolismo , Secuencia de Bases , Computadores , Cristalografía , ADN/metabolismo , Sustancias Intercalantes/farmacología , Matemática , Mitoxantrona , Modelos Moleculares , Conformación Proteica , Difracción de Rayos XAsunto(s)
Antibacterianos/síntesis química , Antivirales/síntesis química , Disulfuros/síntesis química , Oxepinas/síntesis química , Piperazinas/síntesis química , Antibacterianos/farmacología , Antivirales/farmacología , Candida albicans/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Disulfuros/farmacología , Enterovirus/enzimología , Pruebas de Sensibilidad Microbiana , Microsporum/efectos de los fármacos , Mycobacterium/efectos de los fármacos , Oxepinas/farmacología , Phialophora/efectos de los fármacos , Piperazinas/farmacología , Proteus vulgaris/efectos de los fármacos , Staphylococcus/efectos de los fármacos , Streptococcus pyogenes/efectos de los fármacos , Relación Estructura-Actividad , Trichophyton/efectos de los fármacosRESUMEN
A series of 37 anthraquinones were evaluated for their ability to inhibit the induction of cytolytic T-lymphocytes in a mixed lymphocyte culture system, useful as a preliminary screen for immunosuppressive agents. These compounds were also tested for their ability to prevent the production of antibody in mice. It was demonstrated that 1,4-bis [(2-aminoethyl)amino]-5, 8-dihydroxy-9,10-anthracenedione dihydrochloride (AEAD, 2) derived from mitoxantrone (MX, 1) by removing hydroxyethyl groups from both side chains was extremely active in depressing immune responses in vitro and in vivo. Four additional anthraquinones related to AEAD were also identified to share similar suppressive activity. They include a Schiff base, 1,4-dihydroxy-5,8-bis[[2-[(3-pyridinylmethylene)amino]ethyl]amino] -9,10-anthracenedione; a dimer with N-terminals methylated, 1,1-[ethylenebis (iminoethyleneimino)]-bis [5,8-dihydroxy-4-[(2-methylamino-ethyl)amino] anthraquinone tetrahydrochloride; an oxazolidine, 1,4-dihydroxy-5,8-bis [[2-(2-propyl-3-oxazolidinyl)ethyl]amino] anthraquinone; and its polymeric oxazolidine, poly [5,8-dihydroxy-1,4-anthraquinonyleneiminoethylene-3,2-oxazolidine- diyltrimethylene-2,3-oxazolidinediylethyleneimino]. These compounds may warrant further consideration as candidates for the treatment of refractory autoimmune diseases and in organ transplantation.
Asunto(s)
Antraquinonas/farmacología , Terapia de Inmunosupresión , Animales , Formación de Anticuerpos/efectos de los fármacos , Leucemia P388/tratamiento farmacológico , Prueba de Cultivo Mixto de Linfocitos , Ratones , Trasplante de Neoplasias , Relación Estructura-ActividadRESUMEN
Bisamidines of 2,6-diaminoanthraquinone have demonstrated potent activity against cecal and hepatic Entamoeba histolytica infections in rats and hamsters, respectively. A number of these compounds compared favorably, in overall drug efficacy, with metronidazole and other standard agents.