Design, synthesis and biological evaluation of rhein-piperazine-dithiocarbamate hybrids as potential anticancer agents.

A series of novel rhein-piperazine-dithiocarbamate hybrids 3 were efficiently synthesized from rhein through a catalyst-free and one-pot, three-step sequence involving chlorination and N-acylation followed by dithiocarbamate formation. Hybrids 3 were evaluated for their in vitro cytotoxic potency by MTT assay against several human cancer and non-cancer cells. Five of the hybrids were more cytotoxic to human lung cancer cell line A549 than the parent rhein and the reference, cytarabine (CAR). Structure-activity relationship (SAR) analysis indicated that cytotoxicity was significantly enhanced when ester groups were incorporated into the hybrids (3h-j). In particular, hybrid 3h (IC50 = 10.93 µg/mL), containing a long-chain alkyl ester, was the most potent compound toward A549 tumor cells, being 7- and 5-fold more toxic than rhein (IC50 = 77.11 µg/mL) and CAR (IC50 = 49.27 µg/mL), respectively. Additionally, hybrid 3h was less toxic to the corresponding normal human lung fibroblast cell line, WI-38, with a higher selectivity index (SI, WI-38/A549 ≈ 5) than doxorubicin (DOX, SI ≈ 0), CAR (SI ≈ 2) and rhein (SI ≈ 1). Furthermore, hybrid 3h displayed more toxicity against four types of lung cancer cells (A549, Calu-1, PC-9, and H460; IC50 = 10.81-23.78 µg/mL) than against six other types of cancer cells (Huh-7, 786-O, HCT116, Hela, SK-BR-3, and SK-OV-3; IC50 = 23.85-51.98 µg/mL). Further mechanistic studies showed that hybrid 3h induced apoptosis in a concentration-dependent manner in human lung adenocarcinoma cell line PC-9. In vivo safety studies showed that hybrid 3h had no acute toxicity to the major organs of mice and did not lead to blood biochemical index changes. Our results exhibit prominent anti-cancer cell inhibition ability and no obvious systemic toxicity to normal organs, indicating that hybrid 3h has promising potential for further applications in anti-lung cancer drug development.

[Effect of yanggan yishui granule on collagen I, III, and IV, and FN in spontaneously hypertensive rats].

OBJECTIVE: To observe the effect of Yanggan Yishui Granule (YGYSG) on collagen protein I, III, and IV, as well as fibronection (EN) in spontaneously hypertensive rats (SHR), and to explore its possible renal protective mechanisms. METHODS: Fourty SHR were randomly divided into four groups, i.e., the model group, the Benazepril group, the low dose YGYSG group, and the high dose YGYSG group, 10 in each group. A normal control group was set up with recruited Wistar-Kyoto (WKY) rats. After 6 weeks of treatment, the expression of collagen protein I, III, and IV, as well as FN in the 5.1 image analysis system. RESULTS: In the WKY-control group, there was only a small amount of brown particles in the mesenchymal region, the glomerular basement membrane, or the mesangial region. The expression of collagen I, Ill, and IV, as well as EN significantly increased more in the model group than in the normal control group (P < 0.01). After treatment, the expression of collagen I, III, and IV, as well as FN significantly decreased in each treated group, showing statistical difference when compared with the model group (P < 0.01). Besides, decresed expression of collagen I, III, and IV was shown in the low dose YGYSG group and the Benazepril group (P > 0.05). The expression of collagen I, III, and IV could be further reduced in the high dose YGYSG group, showing statistical difference when compared with the Benazepril group and the low dose YGYSG group (P < 0.05, P < 0.01). CONCLUSION: YGYSG might play an important role in the renal protective effect through reducing the synthesis of renal collagen I, III, and IV, as well as FN, increasing the degradation of renal collagen I, III, and IV, as well as FN, thereby reducing excessive deposition of renal extracellular matrix (ECM).