Modelo de investigación oncológica para evaluar medicamentos antitumorales.

En la investigación oncológica el uso de modelos animales es controversial porque es necesario asegurar su bienestar. Se describe un modelo canino basado en biopsias reproductivas (MCBR) de hembras sin enfermedad aparente. El mismo es apto para evaluar terapias con medicamentos a reposicionar como antitumorales. En el MCBR se analizaron cambios morfológicos, variaciones en la expresión inmunohistoquimica de receptores hormonales y niveles de proliferación celular, en biopsias reproductivas (n=42) de tejidos remanentes en castraciones masivas. En una población tratada y otra de control se asociaron cambios en los niveles sanguíneos de hormonas y se correlacionan los resultados con las fases del ciclo estral. Se establecen criterios de exclusión según el ciclo estral y el efecto de la droga. Se administraron las dosis en períodos previamente fijados y se evaluaron en las muestras la expresión de los receptores hormonales y la proliferación mediante el marcador KI67. En los grupos tratados el agliprestone hizo descender la progesterona sérica el día 7 y notablemente en el día 14. En cambio, se registra un mínimo descenso en el grupo control La expresión de RP disminuyó significativamente al día 7 y en el día 14. En tanto en el grupo control aumentó el día 7 y se mantuvo igual en el día 14. Por su parte la expresión de Ki-67, presentó un comportamiento similar. El modelo demostró el papel proliferativo de la progesterona y ser apto para la reposición del aglepristone como adyuvante hormonal posquirúrgico. Se encuentra en estudio el enantato de testosterona con los mismos protocolos

Synthesis and evaluation of the antiviral activity acyclic nucleosides carrying fluorine

-2',3'-Seco nucleosides 5 carrying fluorine and sulfur substituents at C-3' and C-5, respectively, of acyclic sugar moiety were synthesized in enantiomerically and diastereoisomerically pure form. These products and some structurally similar 1',2'-seco-2'-nor-and 1',2'-seco-nucleosides 3 and 4 were tested in vitro for cytotoxicity and antiviral activity. At non-cytotoxic concentrations the compounds were inactive against human immunodeficiency virus and herpes simplex virus type-1

SYNTHESIS, ANTIMICROBIAL AND ANTIVIRAL ACTIVITIES OF ISOTRIMETHOPRIM AND SOME RELATED DERIVATIVES

The synthesis and the antimicrobial activities of 2,4-diamino-6-(3,4.5-trimethoxvbenzyl)pyrimidine (isotrimethoprim) and some related derivatives are reported. The new derivatives have been found scarcely active against bacteria and fungi, with the only exception of 4-chloro-2-methoxypyrimidinyl-3,4,5-trimethoxyphenyldichloromethane, which showed good antibacterial activity against Staphylococcus aureus. Cytotoxicity and antiviral assays, HIV included, have also been determined in comparison with TMP and AZT. Little but selective activity was shown by some derivatives against HIV retrovirus

Pyrazole-related nucleosides. Design, synthesis and antiproliferative activity of methyl 4-Iodo-1-beta-D-ribofuranosylpyrazole-3-carboxylate (IPCAR), and derivatives, against human leukemias, lymphomas and solid tumors cell lines in vitro

A structure-activity relationship (SAR) study on some new 1-beta-D-ribofuranosyl-3,4-substituted pyrazole derivatives led us to obtain 4-iodo-1-beta-D-ribofuranosyl-pyrazole-3-carboxylate (3, IPCAR) and its 3-methyl-1,2,4-oxadiazole analog (11) at position C3. These compounds showed good potency, wide spectrum of antiproliferative activity and low cytotoxicity against resting peripheral blood lymphocytes (PBL). Although none of the test compounds displayed antiviral activity, IPCAR was able to potentiate the anti-HIV-1 activity of dideoxyinosine (ddI), thus behaving like the known inosine monophosphate dehydrogenase (IMPDH) inhibitors ribavirin and tiazofurin. The corresponding methyl esters of the latter two drugs (15 and 16) were also prepared, but they proved inactive. Overall, these results suggest that the target of IPCAR may be an enzyme other than IMPDH involved in the purine de novo biosynthesis

Pyrazole-related nucleosides. Design, synthesis and antiproliferative activity of methyl 4-Iodo-1-beta-D-ribofuranosylpyrazole-3-carboxylate (IPCAR), and derivatives, against human leukemias, lymphomas and solid tumors cell lines in vitro

A structure-activity relationship (SAR) study on some new 1-beta-D-ribofuranosyl-3,4-substituted pyrazole derivatives led us to obtain 4-iodo-1-beta-D-ribofuranosyl-pyrazole-3-carboxylate (3, IPCAR) and its 3-methyl-1,2,4-oxadiazole analog (11) at position C3. These compounds showed good potency, wide spectrum of antiproliferative activity and low cytotoxicity against resting peripheral blood lymphocytes (PBL). Although none of the test compounds displayed antiviral activity, IPCAR was able to potentiate the anti-HIV-1 activity of dideoxyinosine (ddI), thus behaving like the known inosine monophosphate dehydrogenase (IMPDH) inhibitors ribavirin and tiazofurin. The corresponding methyl esters of the latter two drugs (15 and 16) were also prepared, but they proved inactive. Overall, these results suggest that the target of IPCAR may be an enzyme other than IMPDH involved in the purine de novo biosynthesis

Naphthalimido Derivatives as Antifolate Thymidylate Synthase Inhibitors

A new series of N-(substituted)benzyl-1,8-naphthalimides 4, structurally related to the previously reported thymidylate synthase (TS) inhibitor naphthaleins 3, were synthesized and compounds tested for their inhibition of several species of TS. Moreover, their in vitro cytotoxicity together with antimycotic and antibacterial properties were assayed. While no activity was detected in the antibacterial tests, the m-nitro (4ae) and the p-nitro (4af) derivatives were found able to partially inhibit TS at low micromolar concentrations. Introduction of nitro or (substituted)-amino groups in position 4 of the naphthalic ring always led to less active compounds