Alkylating agents from sugars: synthesis of chlorambucil derivatives carried by chiral glycosyl glycerols derived from D-glucosamine

Chlorambucilamide derivatives involving chiral glycosyl glycerols derived from D-glucosamine were synthesized in good yield by coupling the chlorambucil moiety to the amino group of omega-amino-(omega-1)-hydroxyalkyl 2-acylamino-4,6-O-benzylidene-2-deoxy-beta-D-glucopyranosides, and subsequent hydrolysis of the benzylidene group. The starting material was easily available from 2-acetamido-2-deoxy-D-glucose. The bonding of 2,3,4,6-tetra-O-pivaloyl-beta-D-galactopyranosylamine to chlorambucil by formation of an amide function is also described.     

Alkyl and cyclopropyl sugars: approaches to branched-chain D-glucofuranose derivatives

The exocellular d-glucosyltransferase from Streptococcus mutans 6715 has been highly purified with minimal loss of enzymic activity. The organisms were cultured in trypticase soy-broth that had been treated with invertase and filtered through an ultrafilter fitted with a membrane having a cut-off molecular weight at 10,000. To the growth medium was added Tween 80, which prevented the enzyme from aggregating. The final step in the purification employed insoluble, streptococcal dextran as anaffinity support. Two d-glucosyltransferase activities were detected, viz., one that did not adsorb to the insoluble dextran and one that did. The enzymic fraction that had adsorbed to the insoluble dextran in the affinity column was strongly inhibited by added insoluble dextran.     

Alkyl phenols and derivatives from Tapirira obtusa

From the bark of Tapiria obtusa, six alkyl phenol derivatives were isolated: 1-hydroxy-3-[(Z)-7'-nonadecenyl]-benzene, 1-hydroxy-3-[(Z)-7'-heptadecenyl]-benzene, 1-hydroxy-3-[14'-phenyltetradecyl]-benzene, and 1-hydroxy-3-[16'-phenyltetradecyl]-benzene, and their possible biogenetic precursors, 1-(16'-phenyl-12'Z-hexadecenyl)-4-Z-cyclohexene-(1S*,3S*)-diol and (4S*,6S*)-dihydroxy-6-(14'Z-nonadecenyl)-2-cyclohexenone. The structures of these compounds were elucidated by chemical and spectroscopic analysis, (4S*,6S*)-Dihydroxy-6-(14'Z-nonadecenyl)-2-cyclohexenone showed cytotoxic activity.     

Synthesis of nucleosides having unusual branched sugars as potential antiviral agents.

Enantiomerically pure novel nucleosides having unusual branched sugars were synthesized in a stereospecific manner from a common chiral pool of (S, S)-1,4-bis(benzyloxy)-2,3-epoxybutane and evaluated for antiviral activity.     

Naringenin derivatives as anti-atherogenic agents

Two classes of naringenin derivatives were evaluated for anti-atherogenic activity. Naringenin 7-O-oleic ester (2) and naringenin 7-O-cetyl ether (3) inhibited the formation of aortic atherosclerotic lesions in high cholesterol-fed rabbits.     

Alkyl glucosides as effective solubilizing agents for bovine rhodopsin. A comparison with several commonly used detergents.

The suitability of octyl and decyl-beta-D-glucoside as solubilizing agents for the bovine retinal rod outer segment disc membrane was investigated and compared to that of hexadecyltrimethylammonium bromide, N,N-dimethyldodecylamine oxide, Emulphogene BC-720 and digitonin. The properties measured included the thermal stability of rhodopsin, regenerability of bleached rhodopsin by addition of 11-cis-retinal, and the rate of denaturation of bleached rhodopsin as measured by changes in the ultraviolet CD spectrum. Denaturing tendencies of the detergents were also evaluated by observing their effects on the absorption and CD spectra of sperm whale metmyoglobin. Our results demonstrate that octyl glucoside is superior to the other detergents, with the possible exception of digitonin, by the above criteria. Unlike digitonin, however, octyl glucoside affords rapid solubilization of the disc membrane and is itself highly soluble. Decyl glucoside has properties equivalent or superior to octyl glucoside, but salts and buffers interfere with its ability to solubilize the disc membrane. The well defined chemical composition, ease of removal by dialysis, and non-denaturing properties of the alkyl glucosides make them attractive detergents for membrane research.     

One-step synthesis of beta-C-glycolipid derivatives from unprotected sugars

Condensations of nonsymmetrical or symmetrical beta-diketones and unprotected sugars in aq NaHCO3 soln were explored. C-glucosyl and C-maltosyl derivatives bearing lipophilic residue of 8 or 11 carbon atoms were prepared efficiently using this one-step procedure. The amphiphilic properties of these compounds were demonstrated by measuring their CMC.     

Alkyl glucosides as effective solubilizing agents for bovine rhodopsin. A comparison with several commonly used detergents

The suitability of octyl and decyl-β-d-glucoside as solubilizing agents for the bovine retinal rod outer segment disc membrane was investigated and compared to that of hexadecyltrimethylammonium bromide, $\text{N,N-}\text{dimethyldodecylamine}$ oxide, Emulphogene BC-720 and digitonin. The properties measured included the thermal stability of rhodopsin, regenerability of bleached rhodopsin by addition of $\text{11-cis-}\text{retinal}$, and the rate of denaturation of bleached rhodopsin as measured by changes in the ultraviolet CD spectrum. Denaturing tendencies of the detergents were also evaluated by observing their effects on the absorption and CD spectra of sperm whale metmyoglobin. Our results demonstrate that octyl glucoside is superior to the other detergents, with the possible exception of digitonin, by the above criteria. Unlike digitonin, however, octyl glucoside affords rapid solubilization of the disc membrane and is itself highly soluble. Decyl glucoside has properties equivalent or superior to octyl glucoside, but salts and buffers interfere with its ability to solubilize the disc membrane. The well defined chemical composition, ease of removal by dialysis, and non-denaturing properties of the alkyl glucosides make them attractive detergents for membrane research.     

Pregnenolone derivatives as potential anticancer agents

Pregnenolone (1) was used as a template to develop new anticancer compounds. Ring-D modification of 1 resulted in the synthesis of benzylidenes 2-17, pyrazolines 18-76, pyrazoles 85-91, hydrazones 77-84, and oximes 92-107 derivatives. The structure of compound 107 was also deduced through single crystal X-ray diffraction studies. The inclusion of furanyl and pyridyl rings to pregnenolone skeleton increases the cytotoxicity of all compounds significantly. Among benzylidene derivatives, only heterocyclic enone 8 (IC₅₀ = 0.74 μM/mL against HepG2), and 17 (IC₅₀ = 4.49 μM/mL against HepG2, IC₅₀ = 5.01 μM/mL against MDA-MB-230 cancer cell line) exhibited a significant activity. The cytotoxicity data of pyrazoline derivatives 18-76 revealed that only furanyl bearing pyrazolines 40, 42-44, 48, and 49 exhibited significant activities. While all (O-carboxymethyl) oximes, hydazones, and pyrazoles derivatives of pregnenolone did not show any significant activity against both the cell lines. Thus the furanyl bearing enone 8 (IC₅₀ = 0.74 μM/mL against HepG2), and its pyrazoline derivative 48 (IC₅₀ = 0.91 μM/mL against MDA-MB-230 cancer cell lines) were identified as the most active compounds in all derivatives of pregnenolone.     

Quinol derivatives as potential trypanocidal agents

Quinols have been developed as a class of potential anti-cancer compounds. They are thought to act as double Michael acceptors, forming two covalent bonds to their target protein(s). Quinols have also been shown to have activity against the parasite Trypanosoma brucei, the causative organism of human African trypanosomiasis, but they demonstrated little selectivity over mammalian MRC5 cells in a counter-screen. In this paper, we report screening of further examples of quinols against T. brucei. We were able to derive an SAR, but the compounds demonstrated little selectivity over MRC5 cells. In an approach to increase selectivity, we attached melamine and benzamidine motifs to the quinols, because these moieties are known to be selectively concentrated in the parasite by transporter proteins. In general these transporter motif-containing analogues showed increased selectivity; however they also showed reduced levels of potency against T. brucei.     

New imidazolidinedione derivatives as antimalarial agents

A series of new N-alky- and N-alkoxy-imidazolidinediones was prepared and assessed for prophylactic and radical curative activities in mouse and Rhesus monkey models. New compounds are generally metabolically stable, weakly active in vitro against Plasmodium falciparum clones (D6 and W2) and in mice infected with Plasmodium berghei sporozoites. Representative compounds 8e and 9c showed good causal prophylactic activity in Rhesus monkeys dosed 30 mg/kg/day for 3 consecutive days by IM, delayed patency for 19-21 days and 54-86 days, respectively, as compared to the untreated control. By oral, 9c showed only marginal activity in causal prophylactic and radical curative tests at 50 mg/kg/day×3 and 30 mg/kg/day×7 plus chloroquine 10 mg/kg for 7 days, respectively.     

Thiazolyl-pyrazole derivatives as potential antimycobacterial agents

Mycobacterium tuberculosis (Mtb) is an obligate aerobe that is capable of long-term persistence under conditions of low oxygen tension. A series of thiazolyl-pyrazole derivatives (6a–f, 7a–f, 8c, 8e) were screened for antimycobacterial activity against dormant M. tuberculosis H37Ra (D-MTB) and M. bovis BCG (D-BCG). Nine thiazolyl-pyrazole analogs, 6c, 6e, 7a, 7b, 7c, 7e, 7f, 8c and 8e exhibited promissing minimum inhibitory concentration (MIC) values (0.20–28.25?µg/mL) against D-MTB and D-BCG strains of Mtb. Importantly, six compounds (7a, 7b, 7e, 7f, 8c and 8e) exhibited excellent antimycobacterial activity and low cytotoxicity at the maximum evaluated concentration of >250?µg/mL. Finally, the promising antimycobacterial activity and lower cytotoxicity profile suggested that, these compounds could be further subjected for optimization and development as a lead, which could have the potential to treat tuberculosis.     

Novel isoquinoline derivatives as antimicrobial agents

The wide variety of potent biological activities of natural and synthetic isoquinoline alkaloids encouraged us to develop novel antimicrobial isoquinoline compounds. We synthesized a variety of differently functionalized 1-pentyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines (THIQs), including dihydroisoquinolinium salts (2 and 5), methyl pentanoate-THIQ (6), 1-pentanol-THIQ (7), ester derivatives (8–15) and carbamate derivatives (16–23). We employed classic intramolecular Bischler–Napieralski cyclodehydration to generate the isoquinoline core. All the structures were characterized by nuclear magnetic resonance and mass spectrometry. The bactericide and fungicide activities were evaluated for all the synthesized compounds and structure-activity relationships were established. Many compounds exhibited high and broad-range bactericidal activity. Fluorophenylpropanoate ester 13 and the halogenated phenyl- (17, 18) and phenethyl carbamates (21, 22) exerted the most remarkable bactericidal activity. However, few compounds displayed antifungal activity against most of the fungi tested. Among them, chlorinated derivatives like chlorobenzoate and chlorophenylpropanoate esters (10 and 14, respectively) and chlorophenethyl carbamate 22, exhibited the greatest antifungal activity.     

Vancomycin disulfide derivatives as antibacterial agents

A series of lipidated vancomycin analogues 1 bearing disulfide bonds within their lipid chains was designed and synthesized to optimize their ADME profiles while retaining antibacterial potency. These compounds exhibited good activity against resistant organisms and low accumulation in tissues such as kidney and liver.     

Cancer preventive agents 9. Betulinic acid derivatives as potent cancer chemopreventive agents

C-3 esterifications of betulinic acid (BA, 1) and its A-ring homolog, ceanothic acid (CA, 2), were carried out to provide sixteen terpenoids, 4–19, including nine new compounds (4–12). All synthesized compounds were evaluated in an in vitro antitumor-promoting assay using the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Among them, compounds 4–6, 11–14, 16, and 17 displayed remarkable inhibitory effects of EBV-EA activation. BA analog 6, which contains a prenyl-like group, showed the most potent inhibitory effect (100%, 76%, 37%, and 11% inhibition of EBA activation at 1000, 500, 100, and 10 mol ratio/TPA, respectively, with IC₅₀ value of 285 mol ratio/32 pmol TPA). Compound 6 merits further development as a cancer preventive agent.     

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.     

Tubulin-interactive stilbene derivatives as anticancer agents

Microtubules are dynamic polymers that occur in eukaryotic cells and play important roles in cell division, motility, transport and signaling. They form during the process of polymerization of α- and β-tubulin dimers. Tubulin is a significant and heavily researched molecular target for anticancer drugs. Combretastatins are natural cis-stilbenes that exhibit cytotoxic properties in cultured cancer cells in vitro. Combretastatin A-4 (3′-hydroxy-3,4,4′, 5-tetramethoxy-cis-stilbene; CA-4) is a potent cytotoxic cis-stilbene that binds to β-tubulin at the colchicine-binding site and inhibits tubulin polymerization. The prodrug CA-4 phosphate is currently in clinical trials as a chemotherapeutic agent for cancer treatment. Numerous series of stilbene analogs have been studied in search of potent cytotoxic agents with the requisite tubulin-interactive properties. Microtubule-interfering agents include numerous CA-4 and transresveratrol analogs and other synthetic stilbene derivatives. Importantly, these agents are active in both tumor cells and immature endothelial cells of tumor blood vessels, where they inhibit the process of angiogenesis. Recently, computer-aided virtual screening was used to select potent tubulin-interactive compounds. This review covers the role of stilbene derivatives as a class of antitumor agents that act by targeting microtubule assembly dynamics. Additionally, we present the results of molecular modeling of their binding to specific sites on the α- and β-tubulin heterodimer. This has enabled the elucidation of the mechanism of stilbene cytotoxicity and is useful in the design of novel agents with improved anti-mitotic activity. Tubulin-interactive agents are believed to have the potential to play a significant role in the fight against cancer.     

Triaryl methane derivatives as antiproliferative agents

Clotrimazole (CLT) 1, a synthetic anti-fungal imidazole derivative, inhibits tumor cell proliferation and angiogenesis. In the current study, flow cytometric analysis demonstrated that the decrease in tumor cell growth by CLT 1 was associated with inhibition of cell cycle progression at the G(1)-S phase transition, resulting in G(0)-G(1) arrest. A series of CLT 1 analogues has been generated in order to develop CLT 1 derivatives that are devoid of the imidazole moiety which is responsible for the hepatoxicity associated with CLT 1 while retaining CLT 1 efficacy. The majority of these analogues demonstrate in vitro antiproliferative activity ranging from submicromolar to micromolar concentrations.     

Bioactive glasses as delivery systems for antimicrobial agents

Most biomaterial‐associated infections are caused by opportunistic pathogens and bacteria that are regularly found within the microflora of the implant site. In addition, a biomaterial implant or device remains at risk of infection by hematogenous spread of bacteria disseminated from infections elsewhere in the body or from infected peri‐implant tissue in revision surgery. The resulting infections are frequently accompanied by patient morbidity and discomfort and can lead to surgical replacement of the implant after lengthy, unsuccessful attempts to mitigate infections with antibiotic treatments. Therefore, extensive study is aiming to find new infection‐resistant antimicrobial biomaterials and coatings for implants and devices to effectively reduce the incidence of biomaterial‐associated infections. An overview of the in vitro and in vivo antimicrobial efficacies of the numerous biomaterials currently available is beyond the scope of this review. Herein, we provide a comprehensive review of bioactive glasses as biomaterial delivery systems for antimicrobial agents.