Synthesis and structure-activity relationships of antifungal crassinervic acid analogs

A series of analogs of the natural antifungal compound crassinervic acid, a constituent of Piper crassinervium, were synthesized to gain insight into the most relevant structural features affecting the activity of the parent molecule. Most compounds were prepared by aldol reaction of methyl 3-acetyl-4-hydroxybenzoate with a series of ketones, followed by reduction, hydrolysis, and oxidation. The antifungal activities of crassinervic acid and its analogs was assessed against Cladosporium cladosporioides by using the method of bioautography. The bioassay results allowed us to depict structure?activity relationships for this class of compounds.     

Synthesis and structure-activity relationships of 16-modified analogs of 2-methoxyestradiol

A series of 16-modified 2-methoxyestradiol analogs were synthesized and evaluated for antiproliferative activity toward HUVEC and MDA-MB-231 cells, and for susceptibility to conjugation. In addition, the estrogenicity of these analogs was accessed by measuring cell proliferation of the estrogen-dependent cell line MCF7 in response to compound treatment. It was observed that antiproliferative activity dropped as the size of the 16 substituent increased. Selected analogs tested in glucuronidation assays had similar rates of clearance to 2-methoxyestradiol, but had enhanced clearance in sulfonate conjugation assays.     

Synthesis and structure-activity relationships of elafin, an elastase-specific inhibitor.

Elafin, an elastase-specific inhibitor isolated from human skin, and its related peptides were synthesized by the solution procedure, and their inhibitory activities were measured against various enzymes. During the oxidative folding reactions of the reduced peptides, the ratio of the active product to the inactive product was varied by changing the concentration of guanidine HCl and the amount of redox reagents. The disulfide structures of fully active synthetic elafin and the inactive product were determined by amino acid analysis, gas-phase sequencing and mass spectrometry of their proteolytic fragments. The relationship between structure and inhibitory activities and/or the folding reaction was examined and the amino terminal part of the elafin molecule was found to have a great influence on the folding reactions, but not on the inhibitory activities.     

Brassinosteroids and analogs as neuroprotectors: synthesis and structure-activity relationships

We have demonstrated previously that the brassinosteroid (BR) 24-epibrassinolide exerts neuroprotective effects deriving from its antioxidative properties. In this study, we synthesized 2 natural BRs and 5 synthetic analogs and analyzed their neuroprotective actions in neuronal PC12 cells, against 1-methyl-4-phenylpyridinium (MPP(+)), a neurotoxin known to induce oxidative stress and degenerescence of dopaminergic neurons characteristic of Parkinsonian brains. We also tested the neuroprotective potential of 2 commercially available BRs. Our results disclosed that 6 of the 9 BRs and analogs tested protected neuronal PC12 cells against MPP(+) toxicity. In addition, our structure-activity study suggests that the steroid B-ring and lateral chain play an important role for their neuroprotective action.     

Synthesis, cytotoxic activities and structure-activity relationships of topoisomerase I inhibitors: indolizinoquinoline-5,12-dione derivatives

A series of indolizinoquinoline-5,12-dione derivatives (IQDs) are synthesized and evaluated for their cytotoxic activities toward human lung adenocarcinoma (GLC-82), large-cell lung carcinoma (NCI-H460), promyelocytic leukemia (HL-60) and breast carcinoma (MCF-7) cells by MTT method. Most of the IQDs show significant cytotoxic potency. In addition, the evaluation of structure-activity relationships indicated that the incorporation of electron-withdrawing substituents at the C or D ring will enhance the activities of the target compounds distinctly. The topoisomerase I inhibitory activity is also measured.     

Synthesis and structure-activity relationships of novel nikkomycin analogs: inhibitors of the fungal cell wall biosynthesis enzyme chitin synthase.

A series of novel nikkomycin analogs, which inhibited chitin synthase, the fungal cell wall biosynthesis enzyme, has been synthesized and evaluated their inhibitory activities.     

Synthesis and structure-activity relationship of beta-defensins, multi-functional peptides of the immune system.

beta-defensins are a large family of multiple disulfide-bonded peptides occurring in mammals and birds. They play an important role in the innate immune system, directly killing microbial organisms. Recent research has demonstrated that beta-defensins are important for other biological functions beyond antimicrobial effects, including inhibition of viral infection, interaction with Toll-like receptors, chemotactic effects, and sperm function. The corresponding broad spectrum of activities makes this peptide class an important subject and tool in immunologic research. In this review, we summarize the current status of the routes to obtain synthetic beta-defensins, their major structural properties and structure-activity relationship.     

Antifungal sordarins. Synthesis and structure-activity relationships of 3'-O-substituted derivatives.

A number of novel 3'-O-acyl and alkyl sordarins were synthesised for structure-activity relationship studies. Many of these derivatives exhibit high activity against Candida albicans, Candida pseudotropicalis, Candida tropicalis and Cryptococcus neoformans.     

Synthesis and structure-activity relationships of new non-steroidal progesterone receptor ligands.

In order to study structure-activity relationships, a series of new non-steroidal progesterone receptor ligands based on PF1092A was synthesized with structural modifications (mostly introduction or removal of a methyl group) at the 3-, 4-, 5-, 7- or 9-position in the 6-acetoxy-4a, 5, 6, 7-tetrahydro-3, 4a, 5-trimethylnaphtho[2,3-b]furan-2(4H)-one skeleton. Critical positions for high binding affinity to the progesterone receptor were identified.     

Synthesis and structure-activity relationships of novel warfarin derivatives

4-Hydroxycoumarins such as warfarin 1 have been the mainstay of oral anticoagulation therapy for over 20 years. Yet little detail is known about the molecular interactions between 4-hydroxycoumarins with vitamin K epoxide reductase (VKER), inhibition of which produces a deficiency of vitamin K and consequently a deficiency of vitamin K-dependent proteins involved in thrombus formation. Using molecular probes, such as 4-sulfhydrylwarfarin 7 and 4-chlorowarfarin 10 it is shown in vitro that inhibition of VKER by warfarin is dependent on deprotonation of the 4-hydroxycoumarin moiety. In addition, the nature of the substituent on carbon 3 of the 4-hydroxycoumarin modulated inhibition. More specifically, a linear isoprenyl side chain increased inhibition of VKER when compared to cyclical substituents as present in warfarin. An example of a 4-hydroxycoumarin with an isoprenyl side chain is the natural product ferulenol 19 derived from Ferula communis. Ferulenol 19 confers approximately 22 times more potent inhibition than warfarin and is approximately 1.5 more potent than the rodenticide brodifacoum in this in vitro assay. Based on these data it is hypothesized that 4-hydroxycoumarins bind to the active site of VKER thereby mimicking the transition state of the elimination of water from substrate 2-hydroxyvitamin K.     

Synthesis and structure-activity relationships of new second-generation taxoids

A series of second-generation taxoids bearing a substitutent on the C-2-benzoyl group and modifications at C-3′/C-10 positions was synthesized. These taxoids exhibited 2–3 orders of magnitude higher potency than that of paclitaxel against drug-resistant human breast cancer cell lines. It is also noteworthy that three taxoids showed almost no difference in activity against drug-resistant and drug-sensitive cell lines, which are categorized as “advanced second generation taxoids“.     

Synthesis,anticholinesterase activity and structure-activity relationships of m-Aminobenzoic acid derivatives

The synthesis, acetylcholinesterase inhibitory capacity and structure-activity relationships of simple-structured m-Aminobenzoic acid derivatives are reported. Compound 1b was found to be more potent than galanthamine and tacrine in inhibiting acetylcholinesterase.     

Approach to studying the structure-activity relationship of native peptides. I. Structural organization of the opioid peptide Tyr-Glu-Gly-Phe-Met-Arg-Gly-Leu and its artificial analogs]

Theoretical conformational analysis was carried out for the octapeptide Tyr1-Gly2-Gly3-Phe4-Met5-Arg6-Gly7-Leu8. Possible structure of the opioid peptide under physiological conditions may be described by a set of low-energy conformations belonging to 14 different forms of the backbone. The solution of the "reverse conformational problem" for the opioid peptide enables one to predict the modified amino acid sequences (Ala2, D-Ala2, Ala3, D-Ala3, Ala7, D-Ala7, MeMet5, MeArg6-analogues) which may assume one of the low-energy states of the native hormone. The influence of the solute was not taken into account in our calculations.     

Synthesis and structure-activity relationships of open D-Ring galanthamine analogues

Open D-ring galanthamine analogues were prepared using ring-opening reactions of the quaternarized urethane or oxazolidine functions and were evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition potency.     

Synthesis and structure-activity relationships of benzophenone-bearing diketopiperazine-type anti-microtubule agents

KPU-105 (4), a potent anti-microtubule agent that contains a benzophenone was derived from the diketopiperazine-type vascular disrupting agent (VDA) plinabulin 3, which displays colchicine-like tubulin depolymerization activity. To develop derivatives with more potent anti-microtubule and cytotoxic activities, we further modified the benzophenone moiety of 4. Accordingly, we obtained a 4-fluorobenzophenone derivative 16j that inhibited tumor cell growth in vitro with a subnanomolar IC(50) value against HT-29 cells (IC(50)=0.5 nM). Next, the effect of 16j on mitotic spindles was evaluated in HeLa cells. Treatment with 3nM of 16j partially disrupted the interphase microtubule network. By contrast, treatment with the same concentration of CA-4 barely affected the microtubule network, indicating that 16j exhibited more potent anti-mitotic effects than did CA-4.     

Conformation states of thymopentin and its synthetic analogs

Spatial structures of the biologically active fragment Arg-Lys-Asp-Val-Tyr of tymopoetin (tymopentin) and its synthetic analogs: [Lys1-Arg2]-, [Glu3]- and [Gly3] have been investigated by theoretical conformational analysis. These results indicate that the conformational properties of fragments are represented in aqueous solution by five different backbone forms.     

Synthesis and structure-activity relationships of analogs of EM-652 (acolbifene), a pure selective estrogen receptor modulator. Study of nitrogen substitution

EM-652 (acolbifene) analogs have been synthesized as selective estrogen receptor modulators. Substitution on the nitrogen atom of these 2H-1-benzopyran derivatives has been studied for its influence on antiestrogenic activity. Binding to the rat estrogen receptor, inhibition of estradiol-stimulated proliferation of T-47D breast cancer cells, as well as antiuterotrophic and uterotrophic activities in ovariectomized mice have been evaluated. 2H-1-Benzopyran 1b (EM-343, racemic form of EM-652), which contains a piperidine ring, shows the best pharmacological profile; RBA = 380, IC50 value = 0.110 nM (in T-47D cells), as well as 63% and 84% antiuterotrophic inhibitions at the 7.5 and 75 nmol doses, respectively.     

Synthesis and structure-activity relationships of 2',3'-dideoxypurine nucleosides as potential antiretroviral agents.

In order to study the structure-activity relationships of 2',3'-dideoxypurine nucleosides as potential anti-retroviral agents, various purine derivatives have been synthesized and tested against rous sarcoma virus (RSV) in chick embryo fibroblast (CEF) cells, and against human immunodeficiency virus (HIV) in human CD4+ T cells (ATH8). Some of the new purine derivatives found to be significant antiretroviral activities. And the correlations of activity between anti-RSV and anti-HIV have shown fairly good values so far.     

Antifungal sordarins. Synthesis and structure-activity relationships of 3',4'-fused dioxolane and dioxane derivatives.

A number of novel 3',4'-fused dioxolane and dioxane sordarin derivatives were synthesised for structure-activity relationship studies. Many of these derivatives exhibit high activity against Candida spp. and Cryptococcus neoformans.     

Atrial natriuretic peptides. IV. Synthesis and study of shortened analogs]

New analogues of atrial peptides of rat were synthesized by classical methods of peptide chemistry in solution. They contain a D-amino acid residue in the C-terminal part and a residue of mercaptopropionic acid in the N-terminal part of the molecule. Biological activity of the new analogues was studied.