Ruthenium(II) complexes with 6-methyl-2-thiouracil cis -[Ru(6m2tu) 2 (PPh 3 ) 2 ] ( 1 ) and [Ru(6m2tu) 2 (dppb)] ( 2 ) (where PPh 3 = triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane; and 6m2tu = 6-methyl-2-thiouracil) are potent cytotoxic agents and able to bind DNA. The aim of this study was to evaluate in vitro cellular underlying mechanism and in vivo effectiveness of these ruthenium(II) complexes in human acute promyelocytic leukemia HL-60 cells. Both complexes displayed potent and selective cytotoxicity in myeloid leukemia cell lines, and were detected into HL-60 cells. Reduction of the cell proliferation and augmented phosphatidylserine externalization, caspase-3, -8 and -9 activation and loss of mitochondrial transmembrane potential were observed in HL-60 cells treated with both complexes. Cotreatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced Ru(II) complexes-induced apoptosis. In addition, both metal complexes induced phosphorylation of histone H2AX (S139), JNK2 (T183/Y185) and p38α (T180/Y182), and cotreatment with JNK/SAPK and p38 MAPK inhibitors reduced complexes-induced apoptosis, indicating DNA double-strand break and activation of caspase-mediated apoptosis through JNK/p38 pathways. Complex 1 also reduced HL-60 cell growth in xenograft model. Overall, the outcome indicated the ruthenium(II) complexes with 6-methyl-2-thiouracil as a novel promising antileukemic drug candidates.

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Cardiovascular diseases (CVD) are the deadliest noncommunicable disease worldwide. Hypertension is the most prevalent risk factor for the development of CVD. Although there is a wide range of antihypertensive drugs, there still remains a lack of blood pressure control options for hypertensive patients. Additionally, natural products remain crucial to the design of new drugs. The natural product 7-hydroxycoumarin (7-HC) exhibits pharmacological properties linked to antihypertensive mechanisms of action. This study aimed to evaluate the vascular effects of 7-HC in an experimental model of essential hypertension. The isometric tension measurements assessed the relaxant effect induced by 7-HC (0.001 μM–300 μM) in superior mesenteric arteries isolated from hypertensive rats (SHR, 200–300 g). Our results suggest that the relaxant effect induced by 7-HC rely on K+-channels (KATP, BKCa, and, to a lesser extent, Kv) activation and also on Ca2+ influx from sarcolemma and sarcoplasmic reticulum mobilization (inositol 1,4,5-triphosphate (IP3) and ryanodine receptors). Moreover, 7-HC diminishes the mesenteric artery’s responsiveness to α1-adrenergic agonist challenge and improves the actions of the muscarinic agonist and NO donor. The present work demonstrated that the relaxant mechanism of 7-HC in SHR involves endothelium-independent vasorelaxant factors. Additionally, 7-HC reduced vasoconstriction of the sympathetic agonist while improving vascular endothelium-dependent and independent relaxation.

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Introduction: Decreased bioavailability of nitric oxide (NO) plays a mechanistic role in hypertension and myocardial infarction. NO donors are potent vasodilators, but often exhibit toxicity or vascular tolerance. The aim of this study was to investigate the vascular activity possible tachyphylaxis of NONO2P, a novel NO donor. Methods: Male Wistar rats were euthanized, and the superior mesenteric artery was isolated for recordings of isometric force, and in vivo experiments were performed to evaluate blood pressure in non-anesthetized normotensive rats. Results: Cumulative administration of the NONO2P (10 -13 to 3x10 -6 M) induced endothelium-independent relaxation (Emax:111.51 ± 2.31%; pD2: 8.51 ± 0.08, n=9) in arterial rings pre-contracted with phenylephrine (Phe,1μM). However, the relaxation was reduced in pre-contracted rings with Phe exposed to Tyrode's solution containing 20 mM of K + (E max : 102.83 ± 2.10%; pD2: 7.73 ± 0.04, n=6), suggesting the participation of K + channels in the relaxation. The presence of the specific soluble guanylyl cyclase (sGC) inhibitor, ODQ (10μM), abolished the vasorelaxant effect (E max : 15.38 ± 11.85%, n=7). Pre-incubation with cyclopiazonic acid (CPA) (10μM), inhibitor of sarcoendoplasmic reticulum calcium ATPase (SERCA), shifted the relaxation concentration-response to the right (E max : 106.17 ± 3.06%; pD2: 7.69 ± 0.04, n=6). Interestingly, repeated NONO2P administration did not induce tachyphylaxis, and NONO2P presented similar maximum efficacy to sodium nitroprusside (SNP) (E max : 114.24 ± 3.47%; pD2: 9.40 ± 0.04, n=6). Moreover, NONO2P lowered blood pressure in normotensive rats. Conclusion: The endothelium-independent vasorelaxant effect induced by NONO2P involves both sGC, SERCA and K + channel activation, and NONO2P does not appear to cause tachyphylaxis. NONO2P is able to promote vasorelaxation with the same magnitude as SNP. Finally, NONO2P reduces blood pressure, becoming a promising molecule as a novel therapeutic alternative for the treatment of cardiovascular diseases.