Betulinic acid and its derivatives as anti-angiogenic agents

Betulinic acid (1) significantly caused cytotoxicity to endothelial cell line ECV304 (IC(50) 1.26+/-0.44 microg/mL) in a 5-day MTT assay. Novel and more potent derivatives of betulinic acid (2, 4, 6-8) have been synthesized with IC(50) less than 0.4 microg/mL. The endothelial cell specificity against human tumor cell lines DU145, L132, A549, and PA-1 were determined. Further betulinic acid (1) inhibited TLS formation of ECV304 cells on Matrigel(TM) by 5.5% while its derivatives caused an inhibition of 13.1-49.2%.     

Novel bicyclic oxazolone derivatives as anti-angiogenic agents

Novel bicyclic tetrahydropyrano[3,2-d]oxazolones derivatives, analogues of Fumagillin, were synthesised via a stereocontrolled oxidative-rearrangement of furylcarbinols and subsequent treatment with the appropriate isocyanate. These compounds demonstrated potent antiangiogenic activity.     

Evaluation of copper chelation agents as anti-angiogenic therapy

The design, synthesis and evaluation of N,N',N"-tris(2-pyridylmethyl)-cis,cis-1,3,5,-triaminocyclohexane (tachpyr, 1) derivatives as novel anti-angiogenic agents were performed in an in vitro endothelial cell proliferation assay to assess their cytotoxicity and selectivity. The selective nature of the anti-angiogenic agents for human umbilical vein endothelial cells (Huvec) was compared to a normal fibroblast cell line and a human Glioma cell line to evaluate these compounds. N,N',N"-tris(2-mercaptoethyl)-cis,cis-1,3,5-triaminocyclohexane trihydrochloride (3b) was superior to tachpyr in terms of selectivity of its inhibitory activity toward the proliferation of Huvec compared to the fibroblast and human Glioma cell lines.     

Synthesis and evaluation of prodrugs for anti-angiogenic pyrrolylmethylidenyl oxindoles

Potential prodrugs of inhibitors of VEGF-induced angiogenesis have been investigated. The prodrug systems studied were the 4-nitrobenzyl, 2-nitrophenylacetyl and 3-methyl-3-(3,6-dimethylbenzo-1,4-quinon-2-yl)butanoyl groups, readily attached to acidic OH or NH groups in drug molecules, and released upon bioreductive activation. The anti-angiogenic compounds studied were the pyrrolylmethylidenyl oxindole SU5416 (semaxanib) and its novel 6-hydroxy derivative. The potentially pro-anti-angiogenic compounds were assayed for their ability to block VEGF-induced angiogenesis in HUVECS in comparison to the free agents.     

Synthesis and evaluation of quinoline carboxyguanidines as antidiabetic agents

The synthesis and in vivo activities of a series of substituted quinoline carboxyguanidines as a possible novel class of antidiabetic agents is described.     

Synthesis and biological evaluation of thiobenzanilides as anticancer agents

A series of novel thiobenzanilides is described. These compounds have been previously found to show strong biological activity such as antimycotic and antifungal actions. This is the first demonstration on the mechanism of the anticancer effect of thiobenzanilide agents (4a–c) on human melanoma A375 cells. The cytotoxic studies of compounds 4a–c on human melanoma A375 cells indicate thiobenzanilides induced higher cytotoxicity than nitrobenzanilides (3a–c). In addition, DNA flow cytometric analysis shows that 4a–c displays a significant G2/M phase arrest, which progresses to early apoptosis as detected by flow cytometry after double-staining with annexin V and propidium iodide (PI). Because cellular apoptosis is often preceded by the disruption of mitochondrial function, the assessment of mitochondrial function in 4a–c-treated cells is worthy of investigation. Our data revealed that treatment of A375 cells with 4a–c resulted in the loss of mitochondrial membrane potential (ΔΨ_mt), a reduction of ATP synthesis, increased reactive oxygen species (ROS) generation, and activation of caspase-3. Thus, we suggest that 4a–c agents are potent inducers of cell apoptosis in A375 cells.     

Synthesis and evaluation of naphthyridine compounds as antimalarial agents

Primaquine is the drug of choice for the radical cure of Plasmodium vivax malaria, but possesses serious side effects. In this study novel primaquine analogues were designed and synthesized. Lower toxicity was achieved by reducing or eliminating the tendency of forming chemically reactive and toxic intermediates and metabolites. In vitro and in vivo studies found that synthesized compounds were less toxic than the parent compound primaquine, while preserving the desired antimalarial activity. Some of these compounds possess a therapeutic index over 10 times superior to that of the commonly used antimalarial drug chloroquine. These compounds, as well as the underlying design rationale, may find usefulness in the discovery and development of new antimalarial drugs.     

Synthesis and evaluation of myxochelin analogues as antimetastatic agents

Myxochelin A (1) is an inhibitor of tumor cell invasion produced by the bacterium belonging to the genus Nonomuraea. In order to obtain more potent inhibitors, a series of myxochelin analogues [2 and (S)-3–17] were synthesized through the coupling of lysine or diaminoalkane derivatives and appropriately protected hydroxybenzoate, followed by modification of functional groups and deprotection. These compounds were evaluated for their inhibitory activity against invasion of murine colon 26-L5 carcinoma cells. Among the synthetic analogues tested, compound (S)-6 which possesses carbamoyl group at C-1 was found to be the most potent antiinvasive agent and is considered to be a promising lead molecule for the antimetastasis. Compound (S)-6 was also shown to inhibit gelatinase activities of MMP-2 and MMP-9 and in vivo lung metastasis in mice.     

Synthesis and evaluation of functionalized isoindigos as antiproliferative agents

A series of functionalized isoindigos structurally related to meisoindigo (1-methylisoindigo), a therapeutic agent used for the treatment of a form of leukemia, were synthesized and evaluated for antiproliferative activities on a panel of human cancer cells. Two promising compounds (1-phenpropylisoindigo and 1-(p-methoxy-phenethyl)-isoindigo) that were more potent than meisoindigo and comparable to 6-bromoindirubin-3′-oxime on leukemic K562 and liver HuH7 cells were identified. Structure–activity relationships showed the importance of keeping one of the lactam NH in an unsubstituted state. Substitution of the other lactam NH with aryl or arylalkyl side chains retained or improved activity in most instances. An intact exocyclic double bond was also essential, possibly to maintain planarity and rigidity of the isoindigo scaffold. None of the compounds were found to inhibit CDK2 in an in vitro assay, in spite of reports linking the antiproliferative activities of meisoindigo and other isoindigos to CDK2 inhibition. Hence, these functionalized isoindigos disrupted cell growth and proliferation by other mechanistic pathways that did not involve CDK2 inhibition.     

Synthesis and evaluation of original amidoximes as antileishmanial agents

An original series of amidoxime derivatives was synthesized using manganese(III) acetate, Buchwald–Hartwig and Heck reactions. Two amidoximes (39 and 52) showed interesting in vitro activities toward Leishmania donovani promastigotes, exhibiting 8.3 and 8.8 μM IC₅₀ values. Moreover, the cytotoxicity of these compounds was evaluated on human THP1 cells, giving access to the corresponding selectivity index. Among the 25 tested compounds, amidoximes 38 and 39 and diamidoximes 50 and 52 exhibited a better selectivity index than pentamidine used as a drug compound reference.     

Synthesis and evaluation of spiroisoxazoline oxindoles as anticancer agents

Restoring p53 levels through disruption of p53–MDM2 interaction has been proved to be a valuable approach in fighting cancer. We herein report the synthesis and evaluation of eighteen spiroisoxazoline oxindoles derivatives as p53–MDM2 interaction inhibitors. Seven compounds showed an antiproliferative profile superior to the p53–MDM2 interaction inhibitor nutlin-3, and induced cell death by apoptosis. Moreover, proof-of-concept was demonstrated by inhibition of the interaction between p53 and MDM2 in a live-cell bimolecular fluorescence complementation assay.     

Synthesis and evaluation of trehalose-based compounds as anti-invasive agents

Brartemicin is a trehalose-based inhibitor of tumor cell invasion produced by the actinomycete of the genus Nonomuraea. In order to explore the preliminary structure-activity relationship and obtain more potent inhibitors, a series of brartemicin analogs were synthesized through the Mitsunobu coupling of the secondary hydroxyls benzyl protected α,α-d-trehalose with benzoic acid derivatives, followed by modification of functional groups and deprotection. These compounds were evaluated for their inhibitory activity against invasion of murine colon 26-L5 carcinoma cells in vitro. Among the synthetic analogs tested, 6,6′-bis(2,3-dimethoxybenzoyl)-α,α-d-trehalose (5e) was found to be the most potent anti-invasive agent, exhibited a 2.6-fold improvement with regard to the parent natural product brartemicin, and it is considered to be a promising lead molecule for the anti-metastasis.     

Synthesis and biological evaluation of flavonoids as vasorelaxant agents

Several 5,7-dihydroxyflavone and quercetin 3-O-glycosides have been synthesized and evaluated for vasorelaxant activity. A log P-activity relationship amongst flavonoids was suggested.     

Novel pyrazole derivatives: Synthesis and evaluation of anti-angiogenic activity

The synthesis of a series of novel trisubstituted pyrazole derivatives and their PIFA-mediated conversion to molecules bearing the fused pyrazolo[4,3-c]quinoline ring system is reported. The anti-angiogenic activity of these compounds was evaluated by using in vitro assays for endothelial cell proliferation and migration, and in the chicken chorioallantoic membrane (CAM) assay. Compounds containing the fused pyrazolo[4,3-c]quinoline motifs emerged as potent anti-angiogenic compounds, which also had the ability to inhibit the growth of human breast (MCF-7) and cervical (Hela) carcinoma cells in vitro.     

Synthesis and evaluation of pyridinium polyoxometalates as anti-HIV-1 agents

The unique properties of polyoxometalates, such as molecular polarity, redox potential, surface charge distribution, shape and acidity, influence their response of recognition to targeted biological macromolecules. By using PM-19 (K₇PTi₂W₁₀O₄₀) as a lead-compound, a series of novel pyridinium polyoxometalates (A₇PTi₂W₁₀O₄₀), which hadn’t been reported in literatures, were designed and synthesized. The evaluation was conducted using the single-cycle pseudovirus infection assay (TZM-bl assay), CCK-8 method was used for determining the cytotoxicity. The results indicated that the designed pyridinium polyoxometalates had a lower toxicity to TZM-bl cells, and showed higher inhibitory activity against HIV-1 virus.     

Synthesis and biological evaluation of novel pyrrolopyrrolizinones as anticancer agents

We herein describe the synthesis of novel 3-(het)aryl-pyrrolo[2,3-b]pyrrolizin-8(1H)-ones starting from commercial (het)aryl-acetonitriles. A more convergent route was also described through the first synthesis of ethyl 3-amino-4-bromo-1H-pyrrole-2-carboxylate 17. The antiproliferative activities of these compounds were tested toward various cell lines and one of them 10k shows interesting cytotoxic properties, although it was less potent than our lead compound in thiophene series 1k.     

Synthesis and biological evaluation of indolyl chalcones as antitumor agents

A series of indolyl chalcones were synthesized and evaluated in vitro for their anticancer activity against three human cancer cell lines. Compounds 3b–d, 3h, 3j, 3l, 3m, 4g, and 4j showed significant cytotoxicity, particularly, indolyl chalcones 3l and 3m were identified as the most potent and selective anticancer agents with IC₅₀ values 0.03 and 0.09 μM, against PaCa-2 cell line, respectively.     

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 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 of benzamide derivatives and their evaluation as antiprion agents

A new set of 5-(2-(pyrrolidin-1-yl)acetamido)-N-butyl-2-(substituted)benzamide and 5-(2-(piperidin-1-yl)acetamido)-N-butyl-2-(substituted) benzamide derivatives were synthesized in which as structural features the 2-(1-pyrrolidinyl)- or 2-(1-piperidyl)acetylamino group or a diphenylether moiety are associated to a benzamide scaffold. Their binding affinity for human PrP(C) and inhibition of its conversion into PrP(Sc) were determined in vitro; moreover, the antiprion activity was assayed by inhibition of PrP(Sc) accumulation in scrapie-infected mouse neuroblastoma cells (ScN2a) and scrapie mouse brain (SMB) cells. The results clearly indicate the benzamide derivatives as attractive lead compounds for the development of potential therapeutic agents against prion disease.