New triazine derivatives as potent modulators of multidrug resistance

Abstract

A series of 70 triazine derivatives have been synthesized and tested for their capacity to modulate multidrug resistance (MDR) in DC-3F/AD and KB-A1 tumor cells in vitro, in comparison with verapamil (VRP), a calcium channel antagonist currently used in therapy as an antihypertensive drug, which also shows MDR modulating activity. Among the 12 selected compounds, 16 (S9788) showed high MDR reversing properties in vitro (300- and 6-fold VRP at 5 microM in DC-3F/AD and KB-A1 cells, respectively) and induced a strong accumulation of adriamycin. The relationship between the increase of ADR accumulation and the fold reversal induced by these compounds and their lack of effects on the sensitive DC-3F cells suggest that they act mainly by inhibiting the P-glycoprotein (Pgp) catalyzed efflux of cytotoxic agents, as already described for a majority of MDR modulators. In vivo, in association with the antitumor drug vincristine (0.25 mg/kg), 16 (100 mg/kg) increased the T/C by 39% in mice bearing the resistant tumor cell line P388/VCR. According to these interesting properties, 16 was selected for a clinical development because it was more bioavailable than 34, even though it was less active.

Synthesis, Characterization, and Tautomerism of 1,3-Dimethyl Pyrimidine-2,4,6-Trione s-Triazinyl Hydrazine/Hydrazone Derivatives

“…Recently some of 1,3,5-triazine-Schiff base exhibited some activity against Mycobacterium tuberculosis H37Rv [11] and moderate to excellent antiproliferative activity with high selectivity against the human lung cancer cell line H460 [12,13]. Triazine derivatives are widely employed in many biomedical research fields: cancer chemotherapeutic agents [14], multidrug resistance modulators [15], and trifunctional scaffolds in bundle protein preparation [16].…”

Six‐Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

“…The dihydro derivative 250b is more stable and shows potential as an antitumor drug [481]. (251), which is useful in respiratory problems, served as the lead compound to develop triazine derivatives as potent modulators of multidrug resistance in cancer therapy [482]. On the other hand, Melarsoprol (252) (Mel B, Arsobal, Aventis), another derivative of melamine, is one of the drugs licensed for the treatment of sleeping sickness [483].…”

Glicoproteína-P, resistência a múltiplas drogas (MDR) e relação estrutura-atividade de moduladores

“…Em geral, doxorrubicina (adriamicina) é utilizada e a fluorescência é medida em citômetro de fluxo. 48 Ao final do experimento compara-se a reversão (índice de modulação) com o aumento da captação do quimioterápico para determinar a dependência do processo.…”