Synthesis and biological evaluation of helioxanthin analogues

Helioxanthin and analogues have been demonstrated to suppress gene expression of human hepatitis B virus. In the continuous attempt to optimize antiviral activity, various structural motifs were grafted on the helioxanthin scaffold. Many such analogues were synthesized and evaluated for their anti-hepatitis B virus activity. Structure–activity relationships of these helioxanthin derivatives are also discussed. Among these new compounds, 15 exhibits the highest activity against HBV (EC₅₀ = 0.06 μM). This compound can suppress viral surface antigen and DNA expression. Furthermore, viral RNA is also diminished while the core promoter is deactivated upon treatment by 15. A plausible working mechanism is postulated. Our results establish helioxanthin lignans as potent anti-HBV agents with unique mode of action. Since their antiviral mechanism is distinct from current nucleoside/nucleotide drugs, helioxanthin lignans constitute a potentially new class of anti-HBV agents for combination therapy.     

Synthesis and biological evaluation of hydrazidomycin analogues

Hydrazidomycin A is an unusual secondary metabolite of Streptomyces atratus that features a rare enehydrazide core. To learn more about structure–activity relationships of the reported cytotoxic and antiproliferative agent several synthetic routes were explored to synthesize a variety of hydrazidomycin derivatives. Specifically, the size of the side chains, the nature of the double bond and the polar head group were altered. Overall, fourteen analogues were tested for their cytotoxic and antiproliferative effects. Re-examination of synthetic hydrazidomycin A suggests that the antiproliferative activity is attributed to a yet unknown compound that results from degradation or rearrangement. Several of the less complex analogues, however, show antiproliferative activities against individual cancer cell lines and turned out to be more potent than hydrazidomycin A.     

Synthesis and biological evaluation of simplified mycothiazole analogues

Thiazoline and oxazoline analogues of the natural product mycothiazole were synthesized from a common intermediate and evaluated in vitro against HCT-15 colon cancer cells and L(4) larvae of nematode Nippostrongylus brasiliensis. The nature of the heterocyclic moiety seems to modulate the cytotoxic or anthelmintic activity.     

Synthesis and biological evaluation of novel tamoxifen analogues

A collection of compounds, structurally related to the anticancer drug tamoxifen, used in breast cancer therapy, were designed and synthesized as potential anticancer agents. McMurry coupling reaction was used as the key synthetic step in the preparation of these analogues and the structural assignment of E, Z isomers was determined on the basis of 2D-NOESY experiments. The compounds were evaluated for their antiproliferative activity on breast cancer (MCF-7), cervix adenocarcinoma (HeLa) and biphasic mesothelioma (MSTO-211H) human tumor cell lines. The estrogen like properties of the novel compounds were compared with those of the untreated controls using an estrogen responsive element-based (ERE) luciferase reporter assay and compared to 17β-estradiol (E2). Finally, with the aim to correlate the antiproliferative activity with an intracellular target(s), the effect on relaxation activity of DNA topoisomerases I and II was assayed.     

Synthesis and biological evaluation of novel analogues of dictyostatin

Novel analogues of the microtubule-stabilising agent dictyostatin were designed using existing SAR information from the structurally related discodermolide, synthesised by a late-stage diversification strategy and evaluated in vitro for growth inhibition against a range of human cancer cell lines, including those known to exhibit Taxol-resistance (AsPC-1, DLD-1, PANC-1, NCI/ADR).     

Synthesis and biological evaluation of phosphonate analogues of nevirapine

A series of nevirapine-based analogues containing the phosphonate functionality were prepared and evaluated in vitro against HIV RT. The effect of the phosphonate was evaluated against the wild type and Y181C HIV replication. An in vivo PK study was performed on a select analogue.     

Synthesis and preliminary biological evaluation of truncated zoanthenol analogues

Zoanthamines are a family of marine alkaloids that have complex heptacyclic structures and are reported to be interleukin-6 modulators. While the structure of zoanthamines, especially the ABC-ring portion, is similar to that of steroids, the CDEFG-ring portion, composed of aminoacetal and lactone core, is a unique structural element. In this report, we designed and synthesized ABC-ring 6 and CDEFG-ring 7, which are truncated analogues of the northern and southern hemispheres of zoanthenol 5, respectively, and which incorporate all of the functionality of each hemisphere. A preliminary SAR study suggested that the hydrochloride of the CEFG-ring portion is an active pharmacophore for suppressing the growth of interleukin-6-dependent MH60 cells.     

Synthesis and biological evaluation of 3'-carboranyl thymidine analogues

Boron neutron capture therapy (BNCT) is a chemoradio-therapeutic method for the treatment of cancer. It depends on the selective targeting of tumor cells by boron-containing compounds. One category of BNCT agents with potential to selectively target tumor cells may be thymidine derivatives substituted at the 3'-position with appropriate boron moieties. Thus, several thymidine analogues were synthesized with a carborane cluster bound to the 3'-position either through an ether or a carbon linkage. The latter are the first reported carborane-containing nucleosides in which the carboranyl entity is directly linked to the carbohydrate portion of the nucleoside by a carbon-carbon bond. Low but significant phosphorylation rates in the range of 0.18% that of thymidine were observed for the carbon-linked 3'-carboranyl thymidine analogues in phosphoryl transfer assays using recombinant preparations of thymidine kinases 1 (TK1) and thymidine kinases 2 (TK2). Some of the ether-linked 3'-carboranyl thymidine analogues appeared to be slightly unstable under acidic as well as phosphoryl transfer assay conditions and were, if at all, poor substrates for TK1.     

Synthesis and biological evaluation of Ginsenoside Compound K analogues as a novel class of anti-asthmatic agents

Ginsenoside Compound K (CK) showed potent activity against IgE for the treatment of asthma. A series of CK analogues were then synthesized by straightforward procedures. The in vivo anti-IgE activity evaluations using the OVA-induced asthmatic mouse model revealed preliminary SARs of the CK analogues, which showed that the sugar type, modifications on A-ring and the C20 side chain of CK all affected much on the activities. Primary SARs optimization led to the discovery of compounds T1, T2, T3, T8 and T12, which displayed superior or comparable anti-asthmatic effects (IgE value?=?1237.11?±?106.28, 975.82?±?160.32, 1136.96?±?121.85, 1191.08?±?107.59 and 1258.27?±?148.70?ng/mL, respectively) in comparison with CK (1501.85?±?184.66?ng/mL). These potent compounds could serve as leads for further development.     

Synthesis and biological activities evaluation of sanjuanolide and its analogues

Sanjuanolide, psorachalcone A and its seven new analogues were synthesized via a combinatorial strategy by aldol reaction. In order to investigate the effect between electron density in π-conjugated systems and biological activities, several electron-withdrawing and electron-donating groups were introduced at C-4 and the phenolic hydroxyl groups of sanjuanolide. The two natural products and its seven new analogues were investigated for their inhibitory effects against five cancer cell lines. Moreover, the hydroxyisoprenyl group may be important to maintain the biological activities of sanjuanolide.     

Synthesis and biological evaluation of A-ring biaryl-carbamate analogues of rhazinilam

An improvement of the synthesis of biphenyl-carbamate 2a, the most active analogue of rhazinilam 1 so far, was performed using the Pd-catalyzed borylation/Suzuki coupling (BSC) method developed in our laboratories. The preparation of A-ring analogues of 2a bearing electron-withdrawing or donating groups is reported according to this new synthetic scheme. The antitubulin properties as well as the cytotoxicity of these compounds toward human cancer cell lines were evaluated in comparison with rhazinilam and 2a.     

Synthesis and biological evaluation of analogues of bacterial lipid I

Bacterial Lipid I analogues containing different anomeric groups at the muramic acid moiety were synthesized and screened in MurG enzyme assays run in the presence and absence of cell wall membranes. The results obtained in this study help elucidate the role of the lipid diphosphate in the recognition of Lipid I by MurG.     

Synthesis and biological evaluation of piperamide analogues as HDAC inhibitors

Two natural piperamides (piperlonguminine and refrofractamide A) and their derivatives were synthesized and evaluated for inhibitory activity against histone deacetylases, as well as the HCT-116 human colon cancer cell line. The preliminary structure activity relationship was discussed. Compounds featuring a hydroxamic acid moiety exhibited moderate HDAC activity and in vitro cytotoxicity.     

Synthesis and biological evaluation of new mannose 6-phosphate analogues

Three new analogues of mannose 6-phosphate (M6P)—a sulphate and two carboxylates—have been synthesized and their affinity toward the M6P/IGFII receptor evaluated by affinity column chromatography. These compounds display strong binding to the receptor and therefore are new M6P analogues which may find some dermatological applications, for example healing of post-surgical scars.     

Synthesis and biological evaluation of (-)-laulimalide analogues

Analogues of the marine natural product (-)-laulimalide were prepared by total synthesis and evaluated in vitro for anticancer activity.     

Synthesis and biological evaluation of trifluralin analogues as antileishmanial agents

A series of new analogues of trifluralin (TFL) were synthesized and characterized in view of changing the unfavorable properties that limits its use as antileishmanial agent. Some of the TFL analogues display more activity than a standard drug (miltefosine) against the promastigote forms of Leishmania infantum and Leishmania donovani and the intracellular form (THP-1 infected with L. infantum). All analogues showed a clear advantage over miltefosine, as they are not hemolytic. Some analogues can conjugate these characteristics with reduced cell toxicity and improved intracellular activity.     

Synthesis and biological evaluation of longanlactone analogues as neurotrophic agents

Longanlactone analogues were synthesized using a route featuring Friedel-Crafts acylation, Sonogashira coupling and 1,3-dipolar cycloaddition reactions. Structure–activity relationships were investigated for neurotrophic activity. Compound 6 was found to have the most potent neurotrophic activity among all the synthesized analogues in Neuro2a cells as evidenced by a battery of in vitro/cell based assays for assessment of neurogenic and potential neurotrophic activity including neurite outgrowth assay and real time PCR for popular markers of augmented neurotrophic activity. Compound 6 might serve as a template for further development of highly effective neurotrophic molecules.     

Synthesis and biological evaluation of novel 1'-branched and spironucleoside analogues

Novel anomeric spironucleosides and 1'-cyano-2',3'-didehydro-2',3'-dideoxyuridine, a structural analogue of known anti-HIV agents, were prepared by nucleophilic addition of organolithium reagents to 1'-cyano-2'-deoxy- and 1'-cyano-2'-deoxy-2'beta-bromo-uridine derivatives, respectively. The yield and distribution of products depended on the reaction conditions, which were studied in detail. Although none of the compounds exhibited antiviral activity, two compounds displayed cytostatic activity against both murine leukemia and human T-lymphocyte cells.     

Synthesis and biological evaluation of novel 3'-N-tert-butylsulfonyl analogues of docetaxel

Novel 3′-N-tert-butylsulfonyl analogues 10a–c of docetaxel were synthesized and their biological evaluation in cytotoxicity in vitro against several human tumor cell lines were presented. The biologically tested results showed that N-oxide pyridyl substituted10b–c had potent cytotoxicities against human tumor cell lines Eca-109, SKOV3, SMMC-7721, HCT-8, PC3, MCF-7, HeLa and KB.     

Synthesis and biological evaluation of helicid analogues as mushroom tyrosinase inhibitors

A series of helicid analogues were synthesized and evaluated as tyrosinase inhibitors. The results demonstrated that some compounds had more potent inhibitory activities than arbutin (IC(50) 7.3 mM). In particular, compound 1c bearing 4,6-O-benzylidene substituent on the sugar moiety was found to be the most potent inhibitor with IC(50) value of 0.052 mM. The inhibition kinetics analyzed by Lineweaver-Burk plots revealed that helicid analogues were competitive inhibitors. The Circular dichroism spectra indicated that those compounds induced conformational changes of mushroom tyrosinase upon binding.