thiourea and dehydroabietic-acid

A series of DHAA thiourea derivatives containing bisphosphonate moiety were designed and synthesized as potent antitumor agents. Structures of target molecules were confirmed using HR-MS, (1)H NMR and (13)C NMR and they exhibited potent anti-tumor activities against the SK-OV-3, BEL-7404, A549, HCT-116 and NCI-H460 tumor cell lines in vitro. Especially, compound 6e (IC50 = 1.79 ± 0.43 μM) exhibited the best anticancer activity against SK-OV-3 cell line. Its role as an inducer of apoptosis was investigated in this cell line by Annexin-V/PI binding assay and by following its capability for ROS generation, depolarization of mitochondrial transmembrane potential, activation of caspases and expression of pro- and anti-apoptotic proteins. Elevated level of ROS generation, activation of caspase-3, caspase-8, caspase-9, and Fas, higher expression of Bax, lower expression of Bcl-2, and increased level of Bax/Bcl-2 ratio identified 6e as a promising inducer of apoptosis that follows both of the mitochondria dependent pathway and the death receptor-mediated pathway. In addition, the cell cycle analysis indicated that compound 6e caused cell cycle arrest at G1 phase, induced apoptosis and led to cell death by increasing the proportion of sub-G1 cells. Furthermore, molecular docking studies showed that 6e could bind to the ATP pocket sites.

Topics: Abietanes; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Proliferation; Cell Survival; Diphosphonates; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Structure-Activity Relationship; Thiourea; Tumor Cells, Cultured

A series of dehydroabietic acid (DHAA) acyl-thiourea derivatives were designed and synthesized as potent antitumor agents. The in vitro pharmacological screening results revealed that the target compounds exhibited potent cytotoxicity against HeLa, SK-OV-3 and MGC-803 tumor cell lines, while they showed lower cytotoxicity against HL-7702 normal human river cells. Compound 9n (IC50 = 6.58 ± 1.11 μM) exhibited the best antitumor activity against the HeLa cell line and even displayed more potent inhibitory activity than commercial antitumor drug 5-FU (IC50 = 36.58 ± 1.55 μM). The mechanism of representative compound 9n was then studied by acridine orange/ethidium bromide staining, Hoechst 33,258 staining, JC-1 mitochondrial membrane potential staining, TUNEL assay and flow cytometry, which illustrated that this compound could induce apoptosis in HeLa cells. Cell cycle analysis indicated that compound 9n mainly arrested HeLa cells in the S phase stage. Further investigation demonstrated that compound 9n induced apoptosis of HeLa cells through a mitochondrial pathway.

Topics: Abietanes; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; HeLa Cells; Humans; Membrane Potential, Mitochondrial; Mitochondria; Peptides; Thiourea

A series of novel thiourea α-aminophosphonate derivatives containing DHA structure was designed and synthesized as antitumor agents. Their inhibitory activities against the NCI-H460 (lung), A549 (lung adenocarcinoma), HepG2 (liver) and SKOV3 (ovarian) human cancer cell lines were estimated using MTT assay in vitro. The screening results revealed that many compounds exhibited moderate to high levels of antitumor activities against the tested cancer cell lines and that most demonstrated more potent inhibitory activities compared with the commercial anticancer drug 5-fluorouracil. The mechanism of compound 5f was preliminarily investigated by acridine orange/ethidium bromide staining, Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining, TUNEL assay, DNA ladder assay and flow cytometry, which indicated that the compound can induce cell apoptosis in A549 cells.

Topics: Abietanes; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Hep G2 Cells; Humans; Molecular Structure; Organophosphonates; Structure-Activity Relationship; Thiourea

A new class of dehydroabietic amine-substituted primary amine-thiourea bifunctional catalysts were designed and synthesized. The doubly stereocontrolled organocatalytic conjugate addition of a variety of heterocycles-bearing ketones to nitroalkenes was investigated for the first time, affording (S)- or (R)-gamma-nitro heteroaromatic ketones with excellent enantioselectivities (up to ee >99%). Furthermore, the nearly optically pure gamma-nitro heteroaromatic ketones can be readily transformed into chiral pyrrolidine carboxylic acids.

Topics: Abietanes; Amines; Carboxylic Acids; Catalysis; Ketones; Molecular Structure; Pyrrolidines; Stereoisomerism; Thiourea