Total Synthesis of Hapalindole‐Type Natural Products

A unified and bioinspired oxidative cyclization strategy was used in the first total syntheses of naturally occurring 12‐epi‐hapalindole Q isonitrile, hapalonamide H, deschloro 12‐epi‐fischerindole I nitrile, and deschloro 12‐epi‐fischerindole W nitrile, as well as the structural revision of the latter. Hapalindoles H and Q were also synthesized.     

Design, synthesis and antitumor activity of 3-substituted quinolone derivatives (Ⅰ)

A series of quinolone derivatives containing benzimidazole, benzoxazole or benzothiazole ring were synthesized. The cytotoxicity of 12 new compounds was evaluated in KB, Be17402, A2780 and HT-29 cell lines. Most of synthesized compounds showed moderate inhibitory activity against cancer cells. The inhibitory activities of 6k, against KB and A2780 tumor cells are comparable to that of topotecan, one of topoisomerase I inhibitors.     

Design,synthesis and antitumor activity of 3-substituted quinolone derivatives （Ⅰ）

A series of quinolone derivatives containing benzimidazole, benzoxazole or benzothiazole ring were synthesized. The cytotoxicity of 12 new compounds was evaluated in KB, Be17402, A2780 and HT-29 cell lines. Most of synthesized compounds showed moderate inhibitory activity against cancer cells. The inhibitory activities of 6k, against KB and A2780 tumor ceils are comparable to that of topotecan, one of topoisomerase I inhibitors.     

Synthesis and cytotoxic evaluation of novel N-methyl-4-phenoxypicolinamide derivatives

A series of N-methyl-4-phenoxypicolinamide derivatives were synthesized and evaluated in vitro for their cytotoxic activity against A549, H460 and HT29 cell lines. Pharmacological data indicated that some of the target compounds possessed marked antiproliferative activity, superior to that of the reference drug sorafenib. As the most promising compound, 8e exhibited potent cytotoxicity with the IC(50) value of 3.6, 1.7 and 3.0 μM against A549, H460 and HT-29 cell lines, respectively.     

Suberitine A-D, four new cytotoxic dimeric aaptamine alkaloids from the marine sponge Aaptos suberitoides

Suberitine A-D (1-4), four new bis-aaptamine alkaloids with two aaptamine skeleton units, 8,9,9-trimethoxy-9H-benzo[de][1,6]-naphthyridine and demethyl(oxy)-aaptamine, linked through a rare C-3-C-3' or C-3-C-6' σ-bond between the 1,6-naphthyridine rings, together with two known monomers 5 and 6, were isolated from the marine sponge Aaptos suberitoides. Their structures were elucidated using NMR spectroscopy. Compounds 2 and 4 showed potent cytotoxicity against P388 cell lines, with IC(50) values of 1.8 and 3.5 μM, respectively.     

Semisynthetic derivatives of haemanthamine and their in vitro antiproliferative activity evaluation against a panel of human cell lines

In this study, a new series of aliphatic, cyclic, and heterocyclic derivatives of haemanthamine was designed and synthesized to enhance its inhibitory effect on the proliferation and viability of cancer cells. A library of haemanthamine derivatives was subjected to 10 μM single-dose cytotoxicity screening against a panel of human cell lines of various histotypes. Initial cytotoxicity evaluation of the parent haemanthamine (1) and a series of twenty-nine (2–30) semisynthetic analogues showed that for some of the newly formed derivatives, a certain cytotoxic effect was observed, in one case even higher than that of the parent compound. Specifically, 11-O-(4-chloro-3-nitrobenzoyl)haemanthamine (21) showed an enhanced antiproliferative effect, where the mean growth percent (GP) value was 5% compared to haemanthamine, leading to a decrease in the GP to 25%. Among ten cell lines tested, derivative 21, bearing a substituted aromatic ester bond via C-11 of haemanthamine, had excellent activity for inhibiting the growth of HeLa (IC₅₀ = 0.2 ± 0.1 μM), A549 (IC₅₀ = 1.7 ± 0.1 μM) and HT-29 (IC₅₀ = 2.2 ± 0.1 μM) cells. When evaluating response kinetics, we found that 21 and haemanthamine dose- and time-dependently suppressed the proliferation of A549 cells. In contrast to haemanthamine (1), Trypan blue and lactate dehydrogenase (LDH) release assay revealed that 21 was capable of reducing the survival of A549 cells.     

Design, synthesis and cytotoxicity of novel 2-arylvinyl-4-aminoquinoline derivatives

With an aim to develop promising anti-tumor agents, a novel series of 2-arylvinyl-4-aminoquinoline derivatives were designed, synthesized and evaluated for their cytotoxicity against H-460, HT-29, HepG2 and SGC-7901 cell lines in vitro. The pharmacological results indicated that most compounds were more potent than the positive controls, especially compounds 8, 14 and 16 with IC(50) values ranging from 0.05 to 0.85 μM against all tested cell lines respectively, which were 5.7- to 112-fold better than Iressa. The most active compound 14 (IC(50) values of 0.05, 0.25, 0.16, 0.68 μM), bearing 4-fluorostyryl at C-2 position and 3-(dimethylamino)-1-propylamino at C-4 position, showed great promise as a lead for the development of more effective quinoline analogues.     

Design,Synthesis and Pharmacological Evaluation of Novel 4-Phenoxyquinoline Derivatives as Potential Antitumor Agents

A series of novel 4-phenoxyquinoline derivatives containing 3-amino-2-cyano-acrylamide framework was designed and synthesized, and the in vitro cytotoxic activities of them against five cancer cell lines(HT-29, H460, A549, MKN-45, and U87MG) were evaluated. Most of the compounds exhibited moderate-to-significant cytotoxicity and high selectivity against one or more cell lines as compared with Foretinib. The studies of their preliminary structure-activity relationships(SARs) indicate that the compounds containing methyl groups, especially methyl groups at 4-position of the phenyl ring(moiety B) are more effective. Among them, compound 36 shows the most potent antitumor activities with IC₅₀ values of 0.04, 0.09, 0.67, 0.39 and 1.10 μmol/L against HT-29, H460, A549, MKN-45 and U87MG cell lines, respectively.     

New Sesquiterpenes from a Taiwanese Marine Sponge of the Genus Parahigginsia

An undescribed Taiwanese marine sponge of the genus Parahigginsia yielded two new sesquiterpene hydrocarbons-parahigginine ( 1 ) and parahigginone ( 2 ). The structures of the new compounds were established on the basis of NMR spectroscopic and mass spectrometric data. Compounds 1 and 2 exhibited moderate cytotoxicity against murine P-388 and human KB-16, A-549, and HT-29 tumor cells.     

Design,synthesis, and evaluation of novel combretastatin A-4 based chalcone derivatives as anticancer agents

A series of combretastatin A-4 based chalcones ( 14a-l ) were designed, synthesized and these compounds examined for inhibitory effects on the proliferation of human lung (A549), breast (MCF-7), melanoma (A375), and colon (HT-29) carcinoma cells. Compounds 14b , 14c , 14e , 14h , and 14i (tri/dimethoxy, methyl, and mono/dinitro derivatives) have exhibited the most potent antiproliferative activity with IC₅₀ < 2 μM and the hexa methoxy derivative 14b , the most promising one, which displayed the potent inhibitory activities in MCF-7 (IC₅₀: 10 nM), A375 (IC₅₀: 12 nM), and A549 (IC₅₀: 65 nM) cell lines, and is 18 times more potent than the CA-4. Compound 14b represents a new scaffold and the results provide insights into further development of anticancer agents.     

Design, Synthesis and Anticancer Activity of 4-Morpholinothieno[3,2-<i>d</i>]pyrimidine Derivatives Bearing Arylmethylene Hydrazine Moiety

Three series of 4-morpholinothieno[3,2-d]pyrimidine derivatives containing arylmethylene hydrazine moiety (11a-f, 13a-k and 15a-h) were synthesized and their chemical structures as well as the relative stereochemistry were confirmed. The synthesized compounds were evaluated for their cytotoxicity against three cancer cell lines (H460, HT-29, MDA-MB-231). Most of them exhibited moderate to significant cytotoxicity and high-selectivity against one or more cell lines, especially compounds 11c, 13b, 15f and 15g possessing dramatically increased cytotoxicity as compared with the positive controls, which were further evaluated for six other cancer cell lines and one normal cell line. The most promising compound 11c, bearing 3,4-methylenedioxy phenyl group, showed remarkable cytotoxicity against H460, HT-29 and MDA-MB-231 cell lines with IC50 values of 0.003?μM, 0.42?μM and 0.74?μM, which was 1.6- to 290-fold more potent than GDC-0941.     

Golmaenone, a new diketopiperazine alkaloid from the marine-derived fungus Aspergillus sp

A new diketopiperazine alkaloid, golmaenone (1). and related alkaloids, neoechinulin A (2). and L-alanyl-L-tryptophan anhydride (3). have been isolated from the culture broth of the marine-derived fungus Aspergillus sp. The structure and absolute stereochemistry of the new compound (1). was assigned by spectroscopic methods and the advanced Marfey's method. Compounds 1 and 2 exhibited a significant radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) with IC(50) values of 20 and 24 microM, respectively, which are similar to the positive control, ascorbic acid (IC(50), 20 microM). Compounds 1 and 2 also showed an ultraviolet-A (UV-A) (320--390 nm) protecting activity with ED(50) values of 90 and 170 microM, respectively, which are more active than oxybenzone (ED(50), 350 microM) currently being used as sunscreen.     

The structure of a new cardenolide diglycoside and the biological activities of eleven cardenolide diglycosides from Nerium oleander

A new cardenolide diglycoside (1) was isolated from Nerium oleander together with ten known cardenolide diglycosides 2-11. The structure of compound 1 was established on the basis of their spectroscopic data. The in vitro anti-inflammatory activity of compounds 1-11 was examined on the basis of inhibitory activity against the induction of the intercellular adhesion molecule-1 (ICAM-1). Compounds 2-5 were active at an IC(50) value of less than 0.8 μM. The cytotoxicity of compounds 1-11 was evaluated against three human cell lines normal human fibroblast cells (WI-38), malignant tumor cells induced from WI-38 (VA-13), and human liver tumor cells (HepG2). Compound 3 was active toward VA-13 cells, and compounds 2-5 were active toward HepG2 cells at IC(50) values of less than 1.3 μM. The multidrug resistance (MDR)-reversal activity of compounds 1-11 was evaluated on the basis of the amount of calcein in MDR human ovarian cancer 2780AD cells in the presence of each compound. Compounds 1 and 8 showed moderate effects on calcein accumulation.     

Synthesis and cytotoxicity studies of novel [1,2,4]triazolo[1,5-a]pyrimidine-7-amines

A series of novel N-anilino-5-methyl-2-(3-(5-(alkylaminomethyl)furan-2-yl-methylthio)propyl)-[1,2,4]triazolo-[1,5-a]pyrimidine-7-amine derivatives were synthesized and evaluated for their in vitro cytotoxicity against two cancer cell lines, Bel-7402 and HT-1080. Compounds 9, 14, 19 and 23 possessed marked cytotoxicity, especially 23 (with IC(50) values of 15.0 microM and 7.8 microM against Bel-7402 and HT-1080 cell lines, respectively), which had emerged as lead compound. The activity was found to depend strongly on substitution pattern of the side chains at C-2 position, and 4-triflouromethylanilino substituent at C-7 position was an option for anticancer potency.     

Alkaloid extracts of Ficus species and palm oil-derived tocotrienols synergistically inhibit proliferation of human cancer cells

Tocotrienols have been reported to possess anticancer effects other than anti-inflammatory and antioxidant activities. This study explored the potential synergism of antiproliferative effects induced by individual alkaloid extracts of Ficus fistulosa, Ficus hispida and Ficus schwarzii combined with δ- and γ-tocotrienols against human brain glioblastoma (U87MG), lung adenocarcinoma (A549) and colorectal adenocarcinoma (HT-29) cells. Cell viability and morphological results demonstrated that extracts containing a mixture of alkaloids from the leaves and bark of F. schwarzii inhibited the proliferation of HT-29 cells, whereas the alkaloid extracts of F. fistulosa inhibited the proliferation of both U87MG and HT-29 cells and showed synergism in combined treatments with either δ- or γ-tocotrienol resulting in 2.2–34.7 fold of reduction in IC₅₀ values of tocotrienols. The observed apoptotic cell characteristics in conjunction with the synergistic antiproliferative effects of Ficus species-derived alkaloids and tocotrienols assuredly warrant future investigations towards the development of a value-added chemotherapeutic regimen against cancers.     

Design,Synthesis and Antitumor Activity of Novel Indolin-2-one Derivatives Containing 4-Thiazolidinone Moiety

A series of novel indolin-2-one derivatives containing 4-thiazolidinone moiety(7a―7r) were synthesized and evaluated for their in vitro antitumour activities against MDA-MB-231(human breast cancer), H460(human lung cancer) and HT-29(human colon cancer) cell lines by standard 3-(4,5-dimethylthiazae-2-yl)-2,5-diphenyltetrazo- lium bromide(MTT) assay. Representative compounds(7d, 7k, 7m, 7p) with higher cytotoxicity were further examined against one normal cell line(WI-38, human fetal lung fibroblasts). The preliminary investigation shows that most of the compounds display moderate to excellent potency and high selectivity against different human cancer cell lines. In particular, the most potent compound 7m shows promising cytotoxicity against MDA-MB-231, H460 and HT-29 cell lines with IC₅₀ values of 0.78, 0.056 and 0.018 μmol/L, respectively. The potency is much higher than that of Sunitinib(IC₅₀=3.46 μmol/L against MDA-MB-231, IC₅₀=2.59 μmol/L against H460, IC₅₀=1.50 μmol/L against HT-29) by 4.4, 46.3 and 83.3 fold.     

Calaxanthones A-C,three new xanthones from the roots of Calophyllum calaba and the cytotoxicity

Three new xanthones, named calaxanthones A-C (1–3), along with 17 known xanthones (4–20) were isolated from the roots of Calophyllum calaba. Their structures were determined by spectroscopic analysis. All isolated compounds were evaluated for their cytotoxicity against five cancer cell lines (KB, HeLa S-3, HT-29, MCF-7 and HepG-2). Compound 3 showed potent cytotoxicity against all the five cancer cell lines with IC₅₀ values in the range of 0.82–5.04 μM. Furthermore, compound 6 showed potent cytotoxicity against KB, HeLa S-3 and HepG2 cells with IC₅₀ values of 7.06, 5.27 and 9.64 μM, respectively. Additionally, compound 7 showed potent cytotoxicity against KB cell with an IC₅₀ value of 4.62 μM.     

Design,synthesis, and anticancer evaluation of acetamide and hydrazine analogues of pyrimidine

A library of acetamide and hydrazine analogues were generated on the pyrimidine ring through a multistep reaction starting from 5-nitro-pyrimidine-4,6-diol and pyrimidine-4,6-diol, respectively. The synthesized analogues were screened for in vitro cytotoxic activity against various human cancer cell lines like HCT-1 and HT-15 (colon), MCF-7(breast), PC-3 (prostrate), SF268 (CNS) using MTT method. From the bioassay results, it was observed that even though many of the synthesized derivatives exhibited a good potency against various screened cancer cell lines, compound 14a from the acetamide series was found to show potent anticancer activity on all the tested cancer cell lines with IC₅₀ value of 0.36μM on CNS cell line and 1.6μM on HT-21 cell line, and compound 19xxi from hydrazine series of pyrimidine showed potent activity against three tested cancer cell lines with IC₅₀ value of 0.76μM on HT-29 cell line, 2.6μM on HCT-15, and 3.2μM on MCF-7 cell line.     

Phytochemical and cytotoxic investigations of Curcuma mangga rhizomes

Investigations on the cytotoxic effects of the crude methanol and fractionated extracts (hexane, ethyl acetate) C. mangga against six human cancer cell lines, namely the hormone-dependent breast cell line (MCF-7), nasopharyngeal epidermoid cell line (KB), lung cell line (A549), cervical cell line (Ca Ski), colon cell lines (HCT 116 and HT-29), and one non-cancer human fibroblast cell line (MRC-5) were conducted using an in-vitro neutral red cytotoxicity assay. The crude methanol and fractionated extracts (hexane and ethyl acetate) displayed good cytotoxic effects against MCF-7, KB, A549, Ca Ski and HT-29 cell lines, but exerted no damage on the MRC-5 line. Chemical investigation from the hexane and ethyl acetate fractions resulted in the isolation of seven pure compounds, namely (E)-labda-8(17),12-dien-15,16-dial (1), (E)-15,16-bisnor-labda-8(17),11-dien-13-on (2), zerumin A (3), β-sitosterol, curcumin, demethoxycurcumin and bis-demethoxycurcumin. Compounds 1 and 3 exhibited high cytotoxic effects against all six selected cancer cell lines, while compounds 2 showed no anti-proliferative activity on the tested cell lines. Compound 1 also demonstrated strong cytotoxicity against the normal cell line MRC-5. This paper reports for the first time the cytotoxic activities of C. mangga extracts on KB, A549, Ca Ski, HT-29 and MRC-5, and the occurrence of compound 2 and 3 in C. mangga.     

Cattleianal and Cattleianone: Two New Meroterpenoids from Psidium cattleianum Leaves and Their Selective Antiproliferative Action against Human Carcinoma Cells

The Myrteacae family is known as a rich source of phloroglucinols, a group of secondary metabolites with notable biological activities. Leaves of Psidium cattleianum were extracted with chloroform: methanol 8:2 to target the isolation of phloroglucinol derivatives. Isolated compounds were characterized using different spectroscopic methods: nuclear magnetic resonance (NMR), ultra-violet (UV) and mass spectrometry (MS). Two new phloroglucinols were evaluated for cytotoxicity against a panel of six human cancer cell lines, namely colorectal adenocarcinoma cells (HT-29 and HCT-116); hepatocellular carcinoma cells (HepG-2); laryngeal carcinoma (Hep-2); breast adenocarcinoma cells (MCF7 and MDA-MB231), in addition to normal human melanocytes HFB-4. Additionally, cell cycle analysis and annexin-V/FITC-staining were used to gain insights into the mechanism of action of the isolated compounds. The new phloroglucinol meroterpenoids, designated cattleianal and cattleianone, showed selective antiproliferative action against HT-29 cells with IC₅₀’s of 35.2 and 32.1 μM, respectively. Results obtained using cell cycle analysis and annexin-V/FITC-staining implicated both necrosis and apoptosis pathways in the selective cytotoxicity of cattleianal and cattleianone. Our findings suggest that both compounds are selective antiproliferative agents and support further mechanistic studies for phloroglucinol meroterpenoids as scaffolds for developing new selective chemotherapeutic agents.