RESUMEN
To improve cytotoxicity of 10-deoxy-10-C-morpholinoethyl docetaxel analogues against various tumor cell lines including resistant cells expressing P-glycoprotein (P-gp), we modified the 7-hydroxyl group to hydrophobic groups (methoxy, deoxy, 6,7-olefin, alpha-F, 7-beta-8-beta-methano, fluoromethoxy). Among these analogues, the 7-methoxy analogue showed the strongest cytotoxicity. This analogue showed potent activity against B16 melanoma BL6 in vivo by oral administration.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Morfolinas/farmacología , Paclitaxel/análogos & derivados , Paclitaxel/farmacología , Taxoides , Administración Oral , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/farmacología , División Celular/efectos de los fármacos , Técnicas Químicas Combinatorias , Docetaxel , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Melanoma Experimental/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Morfolinas/administración & dosificación , Morfolinas/síntesis química , Paclitaxel/administración & dosificación , Paclitaxel/síntesis química , Solubilidad , Relación Estructura-Actividad , Tasa de Supervivencia , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
Nineteen ring A- and F-modified hexacyclic analogues of camptothecin were synthesized by Friedländer condensation of appropriately substituted bicyclic amino ketones with tricyclic ketone and were evaluated for cytotoxicity and topoisomerase I inhibitory activity. Seventeen of the compounds showed cytotoxic effects comparable or superior to those of 7-ethyl-10-hydroxycamptothecin (SN-38) against mouse leukemia P388 and human tumor cell lines HOC-21 and QG-56. Introduction of a compact and inductively electron-withdrawing substituent such as a hydroxy, methoxy, chloro, or fluoro group into position 5 of ring A of the hexacyclic compound remarkably increased the antitumor activity. The potency of topoisomerase I inhibition of these compounds showed good correlation with their cytotoxicity. Among them, the 4-methyl-5-fluoro hexacyclic compound was the most potent of all and was 10 times as active as SN-38 in in vitro antitumor activity.
Asunto(s)
Antineoplásicos/síntesis química , Camptotecina/análogos & derivados , Inhibidores Enzimáticos/síntesis química , Inhibidores de Topoisomerasa I , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Camptotecina/síntesis química , Camptotecina/química , Camptotecina/farmacología , División Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Irinotecán , Leucemia P388/patología , Ratones , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
An alkylation method of docetaxel at the C-10 position has been established by a radical coupling reaction using a 10-xanthate derivative of 7-O-TES-10-deacetylbaccatin III and appropriate alkenes. In addition the cytotoxic activity of 10-alkylated docetaxel analogs was evaluated. Among these analogs, a derivative having a methoxycarbonyl group at the end of the alkyl moiety exhibited more potent cytotoxic activity than docetaxel.
Asunto(s)
Paclitaxel/análogos & derivados , Taxoides , Alquilación , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/farmacología , Docetaxel , Modelos Moleculares , Paclitaxel/síntesis química , Paclitaxel/química , Paclitaxel/farmacología , Células Tumorales CultivadasRESUMEN
To investigate the role of the 2'-hydroxy group at the C-13 side chain of docetaxel in the antitumor activity, we prepared several 2',2'-difluoro derivatives of docetaxel and evaluated their cytotoxicity against mouse leukemia and human tumor cell lines and their microtubule disassembly-inhibitory activity. These analogues were prepared by esterification of protected 10-deacetylbaccatin III (21) with appropriate alpha, alpha-difluorinated carboxylic acids (Charts 1 and 2). Among these 2',2'-difluorodocetaxel derivatives, 2',2'-difluorodocetaxel (23b) was approximately 3-10 times as active as 2'-fluorodocetaxel (29a) in terms of cytotoxicity. In addition, the 3'-(2-furyl) (23h) and 3'-(2-pyrrolyl) (23p) analogues showed activity comparable or superior to that of docetaxel (2).
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/farmacología , Paclitaxel/análogos & derivados , Taxoides , Animales , Antineoplásicos Fitogénicos/química , Colorantes , Cristalografía por Rayos X , Docetaxel , Humanos , Espectrometría de Masas , Ratones , Microtúbulos/efectos de los fármacos , Paclitaxel/síntesis química , Paclitaxel/química , Paclitaxel/farmacología , Relación Estructura-Actividad , Porcinos , Sales de Tetrazolio , Tiazoles , Tubulina (Proteína)/química , Tubulina (Proteína)/aislamiento & purificación , Células Tumorales CultivadasRESUMEN
CPT-11, a semisynthetic derivative of camptothecin, exhibited strong antitumor activity against lymphoma, lung cancer, colorectal cancer, gastric cancer, ovarian cancer, and cervical cancer. CPT-11 is a pro-drug that is converted to an active metabolite, SN-38, in vivo by enzymes such as carboxylesterase. We synthesized a water-soluble and non-pro-drug analog of camptothecin, DX-8951f. It showed both high in vitro potency against a series of 32 malignant cell lines and significant topoisomerase I inhibition. The anti-proliferative activity of DX-8951f, as indicated by the mean GI50 value, was about 6 and 28 times greater than that of SN-38 or SK&F 10486-A (Topotecan), respectively. These three derivatives of camptothecin showed similar patterns of differential response among 32 cell lines, that is, their spectra of in vitro cytotoxicity were almost the same. The antitumor activity of three doses of DX-8951f administered i.v. at 4-day intervals against human gastric adenocarcinoma SC-6 xenografts was greater than that of CPT-11 or SK&F 10486-A. Moreover, it overcame P-glycoprotein-mediated multi-drug resistance. These data suggest that DX-8951f has a high antitumor activity and is a potential therapeutic agent.
Asunto(s)
Antineoplásicos/farmacología , Camptotecina/análogos & derivados , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/química , Camptotecina/química , Camptotecina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/farmacología , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Solubilidad , Inhibidores de Topoisomerasa I , Trasplante Heterólogo , Células Tumorales Cultivadas/efectos de los fármacos , Agua/químicaRESUMEN
Eleven novel hexacyclic and three 7,9-disubstituted pentacyclic derivatives of camptothecin were synthesized and evaluated for in vitro cytotoxic activity against P388, HOC-21, and QG-56 and in vivo antileukemic activity against P388 in mice. Hexacyclic compounds which have an additional 5-, 6-, or 7-membered ring cyclized at positions 7 and 9 of camptothecin were prepared by intramolecular cyclization of pentacyclic camptothecin derivatives or Friedländer condensation of the appropriate bicyclic amino ketone and tricyclic ketone. All of the hexacyclic compounds exhibited compatible or superior activity of 7-ethyl-10-hydroxycamptothecin (SN-38) in in vitro assays without regard to the size or type of the additional ring, and three of six compounds showed more than 300% T/C on in vivo assay. These results suggest that the potency of the hexacyclic ring system is higher than that of the original pentacyclic ring system of camptothecin and that the conformational rigidity of substituents at positions 7 and 9 is favorable for antitumor activity.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Camptotecina/análogos & derivados , Animales , Camptotecina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Leucemia P388/tratamiento farmacológico , Ratones , Neoplasias Experimentales/tratamiento farmacológico , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/farmacología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Several E-ring-modified analogues of (RS)-camptothecin were synthesized by total synthesis via Friedländer condensation and evaluated for cytotoxicity and antitumor activity against P388 mouse leukemia cells. Among them, (RS)-20-deoxyamino-7-ethyl-10-methoxycamptothecin (25c) was found to be more active than (RS)-camptothecin (1) in the in vivo assay.
Asunto(s)
Antineoplásicos/farmacología , Camptotecina/análogos & derivados , Camptotecina/farmacología , Leucemia P388/tratamiento farmacológico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Camptotecina/síntesis química , Camptotecina/química , Ensayos de Selección de Medicamentos Antitumorales , Espectroscopía de Resonancia Magnética , Ratones , Células Tumorales CultivadasRESUMEN
The camptothecin analogues (+-)-7-ethyl-10-methoxy-20-deoxyaminocamptothecin (2) and (+-)-7-ethyl-10-hydroxy-20-deoxyaminocamptothecin.HCl (3) were synthesized from indolizine compound 4 via Friedländer condensation to construct a pentacyclic ring system, and were tested in a P388 mouse antileukemia assay. Compounds 2 and 3 were more active and less toxic than (+)-camptothecin (1), and therefore had higher therapeutic ratios.