Saravana Kumar Sinniah

Macroline, akuammiline, sarpagine, and ajmaline alkaloids from Alstonia macrophylla

A total of seventeen alkaloids, comprising six macroline (including alstofolinine A, a macroline indole incorporating a butyrolactone ring-E), two ajmaline, one sarpagine, and eight akuammiline alkaloids, were isolated from the stem-bark and leaf extracts of the Malayan Alstonia macrophylla. The structure and relative configurations of these alkaloids were established using NMR, MS and in several instances, confirmed by X-ray diffraction analysis. Six of these alkaloids were effective in reversing multidrug-resistance (MDR) in vincristine-resistant KB cells.

Phenolic content, antioxidant effect and cytotoxic activity of Leea indica leaves

BackgroundThe leaves of Leea indica (Vitaceae), commonly known as ‘Huo Tong Shu’ in Malaysia, have been traditionally used as natural remedy in folk medicine by the locals. The current study reports the outcome of antioxidant and cytotoxic investigation of L. indica leaves. To the best of our knowledge, this is the first report of L. indica leaf crude ethanol and its fractionated extracts (hexane, ethyl acetate and water) for evaluation of total phenolic content, antioxidant effect and cytotoxic activity against colon cancer cell lines.MethodsIn the present study, L. indica leaf crude ethanol and its fractionated extracts (hexane, ethyl acetate and water) were firstly prepared prior to phenolic content, antioxidant effect and cytotoxic activity assessment. Folin-Ciocalteau’s method was used for the measurement of total phenolic content of the extracts. The antioxidant activity was measured by employing three different established testing systems, such as scavenging activity on DPPH (1,1-diphenyl-2-picrylhydrazyl) radicals, reducing power assay and SOD (superoxide dismutase) activity assay. The cytotoxic activity of the extracts were evaluated against three colon cancer cell lines with varying molecular characteristics (HT-29, HCT-15 and HCT-116) by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay.ResultsThe total phenolic content and antioxidant capabilities differed significantly among the L. indica leaf extracts. A strong correlation between total phenolic content and antioxidant properties was found, indicating that phenolic compounds are the major contributor to the antioxidant properties of these extracts. Among the crude ethanol and its fractionated extracts, fractionated water extract showed significantly the highest total phenolic content and strongest antioxidant effect in all the antioxidant testing systems employed in this study. All the four extracts exert no damage to the selected colon cancer cells.ConclusionsThe data obtained in these testing systems clearly establish the antioxidant potency of the fractionated water extract of L. indica leaves. Additional studies should be carried out to isolate and identify the bioactive compounds in the fractionated water extract, in order to provide more convincing evidence.

Acute oral toxicity of Pereskia bleo and Pereskia grandifolia in mice.

Pereskia bleo and Pereskia grandifolia, belonging to the botanical family Cactaceae, have been traditionally used by the locals in Malaysia for treatment of various ailments. The current study reports the outcome of acute oral toxicity investigation of Pereskia bleo and Pereskia grandifolia, on ICR mice. No mortalities or evidence of adverse effects have been observed in ICR mice following acute oral administration at the highest dose of 2500 mg/ kg crude extracts of Pereskia bleo and Pereskia grandifolia. This is the first report on the acute oral toxicity of Pereskia bleo and Pereskia grandifolia and the findings of this study are in agreement with those of in vitro experiments and thus provide scientific validation on the use of the leaves of Pereskia bleo and Pereskia grandifolia.

Synthesis of a DNA-targeting nickel (II) complex with testosterone thiosemicarbazone which exhibits selective cytotoxicity towards human prostate cancer cells (LNCaP).

Testosterone thiosemicarbazone, L and its nickel (II) complex 1 were synthesized and characterized by using FTIR, CHN, (1)H NMR, and X-ray crystallography. X-ray diffraction study confirmed the formation of L from condensation of testosterone and thiosemicarbazide. Mononuclear complex 1 is coordinated to two Schiff base ligands via two imine nitrogens and two tautomeric thiol sulfurs. The cytotoxicity of both compounds was investigated via MTT assay with cisplatin as positive reference standard. L is more potent towards androgen-dependent LNCaP (prostate) and HCT 116 (colon). On the other hand, complex 1, which is in a distorted square planar environment with L acting as a bidentate NS-donor ligand, is capable of inhibiting the growth of all the cancer cell lines tested, including PC-3 (prostate). It is noteworthy that both compounds are less toxic towards human colon cell CCD-18Co. The intrinsic DNA binding constant (Kb) of both compounds were evaluated via UV-Vis spectrophotometry. Both compounds showed Kb values which are comparable to the reported Kb value of typical classical intercalator such as ethidium bromide. The binding constant of the complex is almost double compared with ligand L. Both compounds were unable to inhibit the action topoisomerase I, which is the common target in cancer treatment (especially colon cancer). This suggest a topoisomerase I independent-cell death mechanism.

Tumor suppression effect of Solanum nigrum polysaccharide fraction on Breast cancer via immunomodulation

A polysaccharide fraction from Solanum nigrum, SN-ppF3 was shown previously to have an immunomodulatory activity where it could possibly be used to enhance the host immune response in fighting cancer. The non-toxic SN-ppF3 was fed orally to breast tumor bearing-mice with concentrations of 250 and 500mg/kg for 10days. During the treatment period, size of the tumor and weight of the mice were monitored. At the end of the treatment, blood, tumor, spleen and thymus were harvested for physiological and immunological analyses. After the treatment, the tumor volume and tumor weight were significantly inhibited by 65% and 40%, respectively. Based on the histological observation, the treatment of SN-ppF3 resulted in the disruption of tumor cells morphology. The increase in infiltrating T cells, NK cells and macrophages were observed in tumor tissues of the treated mice, which partly explained the higher apoptosis tumor cells observed in the treated mice. Moreover, the level of TNF-α, IFN-γ and IL-4 were elevated, while the level of IL-6 was decreased significantly, in serum of the treated mice. These results suggested that tumor suppression mechanisms observed in SN-ppF3-treated mice were most probably due through enhancing the host immune response.

Synthesis, characterization and biological evaluation of cationic hydrazone copper complexes with diverse diimine co-ligands

Four new copper(II) complexes containing triphenylphosphonium conjugated salicylaldehyde-(4-fluorobenzhydrazone), (L) with the formulation [CuL]Cl(1), [Cu(phen)L]Cl(2), [Cu(bpy)L]Cl(3), [Cu(dmbpy)L]Cl(4), (where L = doubly deprotonated hydrazone; phen = 1,10′-phenanthroline; bpy = 2,2′-bipyridine; dmbpy = 5,5′-dimethyl-2,2′-bipyridine) have been synthesized. The compounds were characterized by spectroscopic methods and, in the case of crystalline products, by X-ray crystallography. The topoisomerase I (topo I) inhibition, DNA binding and cleavage activities and cytotoxicity of the compounds were studied. A DNA relaxation study demonstrated that all the copper complexes successfully inhibit topo I enzyme by binding to topo I as the preferred pathway. Complex 1 is the most active with starting inhibitory concentration ≈20 μM. The planarity of the tridentate hydrazone Schiff base ligand and the diimine co-ligands increase the binding affinity to DNA. The presence of the 1,10′-phenanthroline co-ligand in complex 2 induces plasmid DNA (pBR322) cleavage without exogenous agents. It is noteworthy that the addition of diimine co-ligands to the copper(II) complex enhanced the cytotoxicity of the compounds, especially against the human prostate adenocarcinoma cell line (PC-3). Complex 2 exhibits the highest activity against PC-3 with the IC50 value of 2.47 ± 0.37 μM. Annexin V/propidium iodide analysis showed that compound 1 induces apoptotic and necrotic cell death, whereas compound 2–4 work mainly through apoptosis.

(3-({(E)-2-((4-Fluorophenyl)carbamothioyl)hydrazinylidene}methyl)-4-hydroxybenzyl) methyltriphenylphosphonium chloride

The cation in the title salt, C33H28FN3OPS+·Cl−, is highly twisted with the phosphonium group occupying a position almost normal to the central hydroxylbenzene ring [P—C—C—C tosrsion angle = −100.9 (3)°], and with the hydrazone substituent twisted out of the plane [C—C—C—N torsion angle = 13.1 (4)°]. The fluorobenzene ring is twisted out of the plane of the adjacent thiourea residue, forming a dihedral angle of 51.69 (10)°. The configuration about the C=N bond [1.281 (4) Å] is E, the O—H and N—H hydrogen atoms are syn, and in the thiourea residue, the N—H hydrogen atoms are anti, allowing for the formation of an intramolecular N—H⋯N hydrogen bond. In the crystal, dimeric aggregates mediated by N—H⋯S bonds are formed, which are linked to the Cl− anions by O—H⋯Cl hydrogen bonds. The four-component aggregates are linked into a three-dimensional structure by C—H⋯Cl interactions.

Thiosemicarbazone Derivative Induces in vitro Apoptosis in Metastatic PC-3 Cells via Activation of Mitochondrial Pathway

BACKGROUND Thiosemicarbazone (TSC) is a Schiff base that has been receiving considerable attention owing to its promising biological implication and remarkable pharmacological properties. The most promising drug candidate of this class would be Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) which has entered phase II clinical trials as a potent anti-cancer chemotherapeutic agent. OBJECTIVE The current research aimed to synthesize several Schiff base ligands from (3-formyl-4-hydroxyphenyl) methyltriphenylphosphonium (T). Additionally, the current research aimed to study the growth inhibitory effect of triphenylphosphonium containing thiosemicarbazone derivatives on PC-3 cells by deciphering the mechanisms involved in cell death. METHOD The compounds were characterized by various spectroscopic methods (infrared spectra, 1H NMR, 13C NMR, HRESIMS and X-ray crystallography) and the results were in conformity with the structure of the targeted compounds. Growth inhibitory effect of the compounds were performed against six human cell lines. RESULTS DM(tsc)T displayed most potent activity against PC-3 cells with IC50 value of 2.64 ± 0.33 μM, surpassing that of the positive control cisplatin (5.47 ± 0.06 μM). There were marked morphological changes observed in DM(tsc)T treated cells stained with acridine orange and ethidium bromide which were indicative of cell apoptosis. Treatment with DM(tsc)T showed that the cell cycle is arrested in the G0/G1 phase after 72 hours. Mitochondrial membrane potential loss was observed in cells treated with DM(tsc)T, indicating the apoptosis could be due to mitochondria mediated pathway. CONCLUSION This study indicates that DM(tsc)T would serve as a lead scaffold for rational anticancer agent development.