Novel diarylsulfonylurea derivatives as potent antimitotic agents

A novel series of diarylsulfonylurea derivatives were synthesized and evaluated for interaction with tubulin and for cytotoxicity against human cancer cell lines. These derivatives demonstrated good inhibitory activity against tubulin polymerization, which was well correlated with promising antiproliferative activity as well as G2/M phase cell cycle arrest. Furthermore, several compounds were also efficacious against multidrug-resistant cancer cells, which are resistant to many other known microtubule inhibitors.     

Novel sulfonate derivatives: potent antimitotic agents.

The synthesis and biological evaluation of novel sulfonate analogues of E-7010 are reported. Several of the compounds are potent inhibitors of cell proliferation and tubulin polymerization. Importantly, these compounds are also active against P-glycoprotein positive (+) cancer cells, which are resistant to many other antitumor agents.     

Synthesis of novel orthoalkylaminophenol derivatives as potent neuroprotective agents in vitro

A series of orthoalkylaminophenol derivatives was synthesized and tested in vitro with respect to their neuroprotective effect. Some of these compounds exhibited a potent antioxidant activity close to that of standard alpha-tocopherol.     

Discovery of novel simplified isoxazole derivatives of sampangine as potent anti-cryptococcal agents

Cryptococcus neoformans is the leading cause of cryptococcal meningitis, which is associated with high mortality due to lack of effective treatment. Herein a series of tricyclic isoxazole derivatives with excellent anti-cryptococcal activities were identified by structural simplification and scaffold hopping of antifungal natural product sampangine. Particularly, compound 8a showed promising features as an anti-cryptococcal lead compound. It was highly active against C. neoformans (MIC₈₀?=?0.031?μg/mL), which was more potent than fluconazole and voriconazole. Moreover, compound 8a showed potent fungicidal activity and had potent inhibitory effects against important virulence factors (i.e. biofilm, melanin and urease) of C. neoformans. Preliminary antifungal mechanism investigation revealed that compound 8a induced apoptosis of C. neoformans cells and arrested the cell cycle at the G1/S phase.     

Design and synthesis of novel spin-labeled camptothecin derivatives as potent cytotoxic agents

In our continuing search for natural product-based spin-labeled antitumor drugs, 20 novel spin-labeled camptothecin derivatives were synthesized via a Cu-catalyzed one pot reaction and evaluated for cytotoxicity against four human tumor cell lines (A-549, MDA-MB-231, KB, and KBvin). Eighteen of the target compounds (9a, 9b, 9d–9k, 9m–9t) exhibited significant in vitro antiproliferative activity against these four tested tumor cell lines. Compounds 9e and 9j (IC₅₀ 0.057 and 0.072 μM, respectively) displayed the greatest cytotoxicity against the multidrug-resistant (MDR) KBvin cell line and merit further development into preclinical and clinical drug candidates for treating cancer including MDR phenotype.     

Sordarin oxazepine derivatives as potent antifungal agents

The synthesis and biological activity of sordarin oxazepine derivatives are described. The key step features a regioselective oxidation of an unprotected triol followed by double reductive amination to afford the ring-closed products. The spectrum of antifungal activity for these novel derivatives includes coverage of Candida albicans, Candida glabrata, and Cryptococcus neoformans.     

Oxime derivatives of sordaricin as potent antifungal agents

Oxime derivatives of the sordarin aglycone have been identified as potent antifungal agents. The in vitro spectrum of activity includes coverage against Candida albicans and Candida glabrata with MICs as low as 0.06 microg/mL. The antifungal activity was established to be exquisitely sensitive to the spatial orientation of the lipophilic side chains.     

Iodine mediated pyrazolo-quinoline derivatives as potent anti-proliferative agents

A novel series of substituted pyrazolo-quinoline derivatives 7pa–7qg were synthesized efficiently by using molecular iodine in DMSO and further characterized based on ¹H NMR, ¹³C NMR, IR and HRMS spectral studies. All the synthesized derivatives were screened for their in vitro cytotoxic activity against a panel of five different cancer cell lines such as A549, HeLa, SKNSH, HepG2 and MCF7. The compounds 7pc, 7pd, and 7pj exhibited considerable to promising anti-proliferative activity with IC₅₀ values of 3.76, 3.87 and 3.83?µM against SKNSH cancer cell line. It was revealed that the compounds 7pa and 7pg have shown very close IC₅₀ values of 2.43 and 6.01?µM, against A549 and MCF7 cancer cell lines respectively, which compared to positive control of Doxorubicin. This is the first report on the synthesis and in vitro anti-proliferative evaluation of pyrazolo-quinoline derivatives.     

Synthesis of novel diaryl ethers and their evaluation as antimitotic agents

A series of novel diaryl ethers possessing various functional groups were synthesized and evaluated for antiproliferative activity in human myeloid leukemia HL-60 cells. Among the compounds examined, compounds 10, 17, 20, 24, and 33 showed moderate to potent antiproliferative activity. These derivatives were further examined in terms of their abilities to inhibit tubulin polymerization; however, all of the tested compounds were relatively ineffective. The reference compound E7010 with an IC(50) of 0.34 microM exhibited potent antiproliferative activity and significantly inhibited tubulin polymerization in a dose-dependent manner.     

Facilely accessible quinoline derivatives as potent antibacterial agents

Quinoline compounds have been extensively explored as anti-malaria and anti-cancer agents for decades and show profound functional bioactivities, however, the studies of these compounds in other medicinal fields have lagged dramatically. In this study, we report the development of a series of facilely accessible quinoline derivatives that display potent antibacterial activity against a panel of multidrug-resistant Gram-positive bacterial strains, especially C. difficile. We also demonstrated that these molecules are effective in vivo against C. difficile. These results revealed that these types of quinoline compounds could serve as prototypes for the development of an appealing class of antibiotic agents used to combat Gram-positive drug-resistant bacterial strains, including C. difficile.     

Aroyl hydrazones of 2-phenylindole-3-carbaldehydes as novel antimitotic agents

Cell cycle arrest of malignant cells is an important option for cancer treatment. In this study, we modified the structure of antimitotic 2-phenylindole-3-carbaldehydes by condensation with hydrazides of various benzoic and pyridine carboxylic acids. The resulting hydrazones inhibited the growth of MDA-MB 231 and MCF-7 breast cancer cells with IC(50) values of 20-30 nM for the most potent derivatives. These 2-phenylindole derivatives also exerted an inhibitory effect on the growth of both proliferating and resting U-373 MG glioblastoma cells. Though the hydrazones exhibited similar structure-activity relationships as the aldehydes, they did not inhibit tubulin polymerization as the aldehydes but were capable of blocking the cell cycle in G(2)/M phase. The cell cycle arrest was accompanied by apoptosis as demonstrated by the activation of caspase-3. Since these 2-phenylindole-based hydrazones display no structural similarity with other antitumor drugs they are interesting candidates for further development.     

Synthesis and evaluation of novel alkannin and shikonin oxime derivatives as potent antitumor agents

A set of forty alkannin and shikonin oxime derivatives were firstly designed and synthesized. Their cytotoxicities against three kinds of tumor cells and a normal cell line were tested and compared with alkannin and shikonin. The cell-based investigation demonstrated that some oxime derivatives were more or comparatively effective to the lead compounds, especially their selective and excellent antitumor activities towards K562 cells with no toxicity in normal cells. We may conclude that oximate modification to the mother nucleus of alkannin and shikonin is an available approach to acquire potent antitumor agents.     

Quinolines derivatives as novel sunscreening agents

Currently, the research and development of sunscreens play an important role on the synthesis of actives that are stable in various kinds of formulations—in addition to their efficiency and broad spectrum of protection against ultraviolet radiation. Our objective here was to synthesize new sunscreening chemical agents using quinoline as a base molecule. Twelve quinoline derivatives were synthesized, four of them novel molecules, and their photoprotective activity was determined in vitro using diffuse transmittance spectrophotometry. We determined their SPF, UVAPF, UVA/UVB ratio, critical wavelength and Boots Star Rating. The quinolines derivatives presented a varied profile of photoprotection, their SPF ranging from 2 to 11 and their UVAPF from 2 to 7. In terms of the critical wavelength, all molecules were considered of broad-spectrum by different classifications. Regarding the Boots Star Rating, one compound received no rating, seven of them received a three stars rating, three received a four stars rating and three were given a five stars rating. The molecules showed in the present work have a wide range of possibilities for creating new sunscreen products, once they have good SPF or UVAPF for single molecules, and they also possess other different qualities that can act synergistically.     

Alkyl-linked bis-THTT derivatives as potent in vitro trypanocidal agents

The effect of several alkyl-linked bis tetrahydro-(2H)-1,3,5-thiadiazine-2-thione (bis-THTT) on Leishmania donovani, Trypanosoma brucei rhodesiense, and Plasmodium falciparum is reported. Most of the compounds exhibited a potent activity against the three parasitic strains but the best in vitro activity profiles were found against T. b. rhodesiense with IC(50) values ranging between 0.3 and 4 microM for the most active compounds.     

Atovaquone derivatives as potent cytotoxic and apoptosis inducing agents

2-Piperazinyl naphthoquinones (2) and 2-piperidinyl naphthoquinones (3) were designed and synthesized as new cytotoxic and apoptosis inducing agents by utilizing the anti-parasite drug atovaquone as lead compound. Several compounds displayed significantly improved cytotoxic activities against a panel of cancer cell lines than that of atovaquone. These compounds also induced apoptosis through activating pro-apoptotic caspases 9 and 3.     

Design, synthesis, and evaluation of novel kazusamycin A derivatives as potent antitumor agents

Novel kazusamycin A derivatives were designed in the viewpoint of decrease of reactivity at the alpha,beta-unsaturated delta-lactone moiety against Michael-type addition. Although 25-30 steps were required for the synthesis of each compound, their syntheses were achieved. Cytotoxicity against HPAC cell line was evaluated, and two of them exhibited comparable potency to kazusamycin A. Hepatic toxicity of these designed compounds was much lower than that of kazusamycin A.     

Development of novel phenoxy-diketopiperazine-type plinabulin derivatives as potent antimicrotubule agents based on the co-crystal structure

The co-crystal structure of Compound 6b with tubulin was prepared and solved for indicating the binding mode and for further optimization. Based on the co-crystal structures of tubulin with plinabulin and Compound 6b, a total of 27 novel A/B/C-rings plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human lung cancer NCI-H460 cell line. The optimum phenoxy-diketopiperazine-type Compound 6o exhibited high potent cytotoxicity (IC₅₀ = 4.0 nM) through SAR study of three series of derivatives, which was more potent than plinabulin (IC₅₀ = 26.2 nM) and similar to Compound 6b (IC₅₀ = 3.8 nM) against human lung cancer NCI-H460 cell line. Subsequently, the Compound 6o was evaluated against other four human cancer cell lines. Both tubulin polymerization assay and immunofluorescence assay showed that Compound 6o could inhibit microtubule polymerization efficiently. Furthermore, theoretical calculation of the physical properties and molecular docking were elucidated for these plinabulin derivatives. The binding mode of Compound 6o was similar to Compound 6b based on the result of molecular docking. The theoretical calculated LogPo/w and PCaco of Compound 6o were better than Compound 6b, which could enhance its cytostatic activity. Therefore, Compound 6o might be developed as a novel potent anti-microtubule agent.     

Comparative QSAR modelling of 2-phenylindole-3-carbaldehyde derivatives as potential antimitotic agents

QSAR modelling was done on some 2-phenylindole-3-carbaldehyde derivatives to find out structural requirements for more active antimitotic agents. Four statistical methods were used to develop models. The results show the importance of ETSA indices, RTSA indices, IC1, SIC4, Jhetv and MSD on the activity. Electrostatic potential charges of atoms, increased surface area, and presence of bulky group along Y-axis and chlorine substitution were also found to be important.