ABSTRACT
Lysicamine is a natural oxoaporphine alkaloid, which isolated from traditional Chinese medicine (TCM) herbs and has been shown to possess cytotoxicity to hepatocarcinoma cell lines. Reports on its antitumor activity are scarce because lysicamine occurs in plants at a low content. In this work, we demonstrate a facile concise total synthesis of lysicamine from simple raw materials under mild reaction conditions, and the preparation of the Ru(II), Rh(III), Mn(II) and Zn(II) complexes 1-4 of lysicamine (LY). All the compounds were fully characterized by elemental analysis, IR, ESI-MS, 1H and 13C NMR, as well as single-crystal X-ray diffraction analysis. Compared with the free ligand LY, complexes 2 and 3 exhibited superior in vitro cytotoxicity against HepG2 and NCI-H460. Mechanistic studies indicated that 2 and 3 blocked the cell cycle in the S phase by decreasing of cyclins A2/B1/D1/E1, CDK 2/6, and PCNA levels and increasing levels of p21, p27, p53 and CDC25A proteins. In addition, 2 and 3 induced cell apoptosis via both the caspase-dependent mitochondrial pathway and the death receptor pathway. in vivo study showed that 2 inhibited HepG2 tumor growth at 1/3 maximum tolerated dose (MTD) and had a better safety profile than cisplatin.
ABSTRACT
OBJECTIVE: To investigate the clinical and neurodevelopmental profiles of patients with biotinidase deficiency and to determine the efficacy of current therapy with respect to outcome. METHODS: Six patients aged from 3 months to 14 years with biotinidase deficiency were confirmed by urinary organic acid analysis with gas chromatography/mass spectrometry (GC/MS) and biotinidase assay on dried blood spots. Biotin was supplemented individually (10-40 mg/d). Their clinical features, laboratory findings, and treatment regimen were reviewed. RESULTS: All the 6 patients presented with some extent of neurological abnormalities and dermatological lesions. Cases 1 - 3 had poor feeding, vomiting, seizures, mental retardation, and lethargy onset from their early infancy, with varied degree of anemia, ketosis, acidosis, and hypoglycemia. Case 2 exhibited eczema and dermatitis from his age of 7 months. Case 4 displayed motor deficit and ataxia after 6 months of age, and generalized pustular psoriasis when he was 8 months old. Cases 5 and 6 gradually showed muscle weakness and paraplegia at the age of 7 years and 5 years, respectively. Inflammatory demyelination changes of cervical cord were evident on magnetic resonance imaging in these two patients. Case 6 had progressive optic atrophy, eczema and alopecia. Remarkable elevations of urinary lactate, pyruvate, 3-OH-propionate, methylcitrate, propionylglycine, 3-OH-isovalerate, 3-methylcrontonylglycine were confirmed in cases 1, 2, 3 and 5. Slight increase of urinary lactate, pyruvate, and 3-methylcrontonylglycine was observed in cases 4 and 6. Biotinidase activities assayed on dried blood spots from all the patients were below 0.1 pmol/(min.3 mm) Biotin supplementation for all the patients, except for case 3 who was not treated, resulted in pronounced and rapid clinical and biochemical improvement. Cases 4 and 6 had residual neurological damage comprising ataxia and motor handicap of legs, due to prolonged disease course. CONCLUSIONS: Biotinidase deficiency intensively impairs nervous system and skin in the affected patients. Urinary organic acid analysis and blood biotinidase assay are crucial to the diagnosis. Early diagnosis and biotin supplementation can contribute significantly to the improvement of prognosis.