RESUMEN
A new biotest system was developed based on highly proliferating human cell cultures (lines LNCaP and PC-3). With the help of this system, two known synthetic polyamines--alpha-difluoromethylornithine (DFMO) and methylglioxalbis(guanylhydrason) (MGBG)--as well as four new synthetic analogues difenyl containing amines (DFCA-1-DFCA-4) with molecular weights of 725.5 (DFCA-1), 755.5 (DFCA-2), 655.5 (DFCA-3), and 681.5 Da (DFCA-4) were tested. In this biotest system, DFMO (0.1-400 microM) did not reveal functional activity, whereas for MGBG a cytotoxic effect was registered (100-200 microM). DFCA-1, DFCA-2, and DFCA-4 had a similar effect at concentrations of 10 microM and higher; DFCA-3, at a concentration of 50 microM and higher. Thus, DFCA-1 has a higher level of antiproliferating activity and may be considered as the most potent cytostatic agent.
Asunto(s)
Compuestos de Bifenilo/farmacología , Citostáticos/farmacología , Eflornitina/farmacología , Mitoguazona/farmacología , Poliaminas/farmacología , Bioensayo , Compuestos de Bifenilo/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citostáticos/síntesis química , Eflornitina/síntesis química , Humanos , Masculino , Mitoguazona/síntesis química , Poliaminas/síntesis química , Relación Estructura-ActividadRESUMEN
The purpose of this study was to synthesize a series of delta-amide derivatives of the antitrypanosomal drug eflornithine (2,5-diamino-2-(difluoromethyl)pentanoic acid hydrochloride, DMFO, CAS 70052-12-9), to determine their physicochemical properties and to assess whether they convert to eflornithine in vivo and if so, whether higher systemic exposure to eflornithine could be achieved by increase intestinal absorption, suggesting an oral treatment to be possible. The derivatives were synthesized by amidation of eflornithine on its delta-amino group using acyl chlorides. The partition coefficients (log D, pH = 7.4) were found to be between -0.78 +/- 1.07 and -0.07 +/- 1.08 while the aqueous solubility (Sw), which as determined in phosphate buffered solution (pH 7.4), ranged from 11.13 +/- 0.32 to 28.74 +/- 0.36 mg/mL. The synthesized compounds were thus mostly more lipophilic than eflornithine itself (log D = -0.98 +/- 0.88, Sw = 34.96 +/- 0.37 mg/mL). The intestinal absorption was assessed by plasma analysis after oral administration of each compound to Sprague-Dawley rats. The biological data revealed that the derivatives were either not absorbed from the gastro-intestinal tract or not metabolized into eflornithine as no parent drug was detected in the plasma.