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1.
Lipids ; 52(6): 535-548, 2017 06.
Article in English | MEDLINE | ID: mdl-28523480

ABSTRACT

The naturally occurring (6Z)-(±)-2-methoxy-6-hexadecenoic acid (1) and (6Z)-(±)-2-methoxy-6-octadecenoic acid (2) were synthesized in 7-8 steps with 38 and 13% overall yields, respectively, by using an acetylide coupling approach, which made it possible to obtain a 100% cis-stereochemistry for the double bonds. In a similar fashion, the acetylenic analogs (±)-2-methoxy-6-hexadecynoic acid (3) and (±)-2-methoxy-6-octadecynoic acid (4) were also synthesized in 6-7 steps with 48 and 16% overall yields, respectively. The antibacterial activity of acids 1-4 was determined against clinical isolates of methicillin-resistant Staphylococcus aureus (ClMRSA) and Escherichia coli. Among the series of compounds, acid 4 was the most active bactericide towards CIMRSA displaying IC50s (half maximal inhibitory concentrations) between 17 and 37 µg/mL, in sharp contrast to the 6-octadecynoic acid, which was not bactericidal at all. On the other hand, acids 1 and 3 were the only acids that displayed antibacterial activity towards E. coli, but 1 stood out as the best candidate with an IC50 of 21 µg/mL. The critical micelle concentrations (CMCs) of acids 1-4 were also determined. The C18 acids 2 and 4 displayed a five-fold lower CMC (15-20 µg/mL) than the C16 analogs 1 and 3 (70-100 µg/mL), indicating that 4 exerts its antibacterial activity in a micellar state. None of the studied acids were inhibitory towards S. aureus DNA gyrase discounting this type of enzyme inhibition as a possible antibacterial mechanism. It was concluded that the combination of α-methoxylation and C-6 unsaturation increases the bactericidal activity of the C16 and C18 FA towards the studied bacterial strains. Acids 1 and 4 stand out as viable candidates to be used against E. coli and CIMRSA, respectively.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Escherichia coli/drug effects , Fatty Acids, Monounsaturated/chemistry , Fatty Acids, Monounsaturated/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemical synthesis , Escherichia coli Infections/drug therapy , Fatty Acids, Monounsaturated/chemical synthesis , Humans , Staphylococcal Infections/drug therapy
2.
Lipids ; 51(2): 245-56, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26694606

ABSTRACT

The novel fatty acids (2R,5Z,9Z)-2-methoxy-25-methyl-5,9-hexacosadienoic acid (1a) and (2R,5Z,9Z)-2-methoxy-24-methyl-5,9-hexacosadienoic acid (1b) were isolated in 80 % purity from the Caribbean sponge Asteropus niger by chloroform/methanol extraction followed by solvent partitioning and silica gel column chromatography. The compounds were characterized by utilizing a combination of gas chromatography-mass spectrometry, nuclear magnetic resonance, and circular dichroism. Acids 1a and 1b were not detected in the phospholipids (PtdCho and PtdIns) of the sponge, but rather as free FA and possibly in glycosylceramides. The mixtures of 1a and 1b displayed cytotoxicity towards THP-1 and HepG2 cells with EC50's between 41 and 35 µg/mL. Apoptosis was not the preferred mode of cell death induced by 1a-1b in the THP-1 cells. This implies other types of cytotoxicity mechanisms, such as membrane disruption and/or the inhibition (EC50 = 1.8 µg/mL) of the human topoisomerase IB enzyme (hTopIB), with a mechanism of inhibition different from the one displayed by camptothecin (CPT). In a separate experiment, the mixture of 1a and 1b also displayed cytotoxicity towards ex vivo mouse splenocytes infected with Leishmania infantum amastigotes (IC(50) = 0.17 mg/mL) and free living promastigotes (IC(50) = 0.34 mg/mL). It was also found that the FA were inhibitory of the Leishmania topoisomerase IB (LTopIB) with an EC(50) = 5.1 µg/mL. Taken together, 1a and 1b represent a new class of FA with potential as TopIB inhibitors that preferentially inhibit hTopIB over LTopIB.


Subject(s)
DNA Topoisomerases/biosynthesis , Fatty Acids, Unsaturated/chemistry , Glycosphingolipids/chemistry , Leishmaniasis, Visceral/drug therapy , Porifera/chemistry , Animals , DNA Topoisomerases/chemistry , Fatty Acids, Unsaturated/pharmacology , Gas Chromatography-Mass Spectrometry , Hep G2 Cells , Humans , Leishmania infantum/drug effects , Leishmania infantum/pathogenicity , Leishmaniasis, Visceral/parasitology , Magnetic Resonance Spectroscopy , Mice , Topoisomerase Inhibitors/chemistry , Topoisomerase Inhibitors/pharmacology
3.
Bioorg Med Chem Lett ; 25(22): 5067-71, 2015 Nov 15.
Article in English | MEDLINE | ID: mdl-26483137

ABSTRACT

The first total synthesis of a C5-curcumin-2-hexadecynoic acid (C5-Curc-2-HDA, 6) conjugate was successfully performed. Through a three-step synthetic route, conjugate 6 was obtained in 13% overall yield and tested for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains. Our results revealed that 6 was active against eight MRSA strains at MICs that range between 31.3 and 62.5 µg/mL. It was found that the presence of 2-hexadecynoic acid (2-HDA, 4) in conjugate 6 increased 4-8-fold its antibacterial activity against MRSA strains supporting our hypothesis that the chemical connection of 4 to C5-curcumin (2) increases the antibacterial activity of 2 against Gram-positive bacteria. Combinational index (CIn) values that range between 1.6 and 2.3 were obtained when eight MRSA strains were treated with an equimolar mixture of 2 and 4. These results demonstrated that an antagonistic effect is taking place. Finally, it was investigated whether conjugate 6 can affect the replication process of S. aureus, since this compound inhibited the supercoiling activity of the S. aureus DNA gyrase at minimum inhibitory concentrations (MIC) of 250 µg/mL (IC50=100.2±13.9 µg/mL). Moreover, it was observed that the presence of 4 in conjugate 6 improves the anti-topoisomerase activity of 2 towards S. aureus DNA gyrase, which is in agreement with results obtained from antibacterial susceptibility tests involving MRSA strains.


Subject(s)
Alkynes/pharmacology , Anti-Bacterial Agents/pharmacology , Curcumin/analogs & derivatives , DNA, Superhelical/chemistry , DNA, Superhelical/pharmacology , Fatty Acids, Unsaturated/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Alkynes/chemistry , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/toxicity , Chlorocebus aethiops , Curcumin/chemical synthesis , Curcumin/pharmacology , Curcumin/toxicity , DNA Gyrase/chemistry , Escherichia coli/drug effects , Fatty Acids, Unsaturated/chemistry , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Staphylococcus aureus/enzymology , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacology , Topoisomerase II Inhibitors/toxicity , Vero Cells
4.
Chem Phys Lipids ; 178: 84-91, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24365283

ABSTRACT

The first study aimed at determining the structural characteristics needed to prepare antibacterial 2-alkynoic fatty acids (2-AFAs) was accomplished by synthesizing several 2-AFAs and other analogs in 18-76% overall yields. Among all the compounds tested, the 2-hexadecynoic acid (2-HDA) displayed the best overall antibacterial activity against Gram-positive Staphylococcus aureus (MIC=15.6 µg/mL), Staphylococcus saprophyticus (MIC=15.5 µg/mL), and Bacillus cereus (MIC=31.3 µg/mL), as well as against the Gram-negative Klebsiella pneumoniae (7.8 µg/mL) and Pseudomonas aeruginosa (MIC=125 µg/mL). In addition, 2-HDA displayed significant antibacterial activity against methicillin-resistant S. aureus (MRSA) ATCC 43300 (MIC=15.6 µg/mL) and clinical isolates of MRSA (MIC=3.9 µg/mL). No direct relationship was found between the antibacterial activity of 2-AFAs and their critical micelle concentration (CMC) suggesting that the antibacterial properties of these fatty acids are not mediated by micelle formation. It was demonstrated that the presence of a triple bond at C-2 and the carboxylic acid moiety in 2-AFAs are important for their antibacterial activity. 2-HDA has the potential to be further evaluated for use in antibacterial formulations.


Subject(s)
Drug Resistance, Multiple/drug effects , Fatty Acids, Unsaturated/chemistry , Fatty Acids, Unsaturated/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Fatty Acids, Unsaturated/chemical synthesis , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests
5.
Mar Drugs ; 11(10): 3661-75, 2013 Sep 30.
Article in English | MEDLINE | ID: mdl-24084785

ABSTRACT

Sponges biosynthesize α-methoxylated fatty acids with unusual biophysical and biological properties and in some cases they display enhanced anticancer activities. However, the antiprotozoal properties of the α-methoxylated fatty acids have been less studied. In this work, we describe the total synthesis of (5Z,9Z)-(±)-2-methoxy-5, 9-eicosadienoic acid (1) and its acetylenic analog (±)-2-methoxy-5,9-eicosadiynoic acid (2), and report that they inhibit (EC50 values between 31 and 22 µM) the Leishmania donovani DNA topoisomerase IB enzyme (LdTopIB). The inhibition of LdTopIB (EC50 = 53 µM) by the acid (±)-2-methoxy-6-icosynoic acid (12) was studied as well. The potency of LdTopIB inhibition followed the trend 2 > 1 > 12, indicating that the effectiveness of inhibition depends on the degree of unsaturation. All of the studied α-methoxylated fatty acids failed to inhibit the human topoisomerase IB enzyme (hTopIB) at 100 µM. However, the α-methoxylated fatty acids were capable of inhibiting an active but truncated LdTopIB with which camptothecin (CPT) cannot interact suggesting that the methoxylated fatty acids inhibit LdTopIB with a mechanism different from that of CPT. The diunsaturated fatty acids displayed low cytotoxicity towards Leishmania infantum promastigotes (EC50 values between 260 and 240 µM), but 12 displayed a better cytotoxicity towards Leishmania donovani promastigotes (EC50 = 100 µM) and a better therapeutic index.


Subject(s)
Camptothecin/pharmacology , Fatty Acids, Unsaturated/chemistry , Fatty Acids, Unsaturated/pharmacology , Leishmania donovani/drug effects , Topoisomerase I Inhibitors/chemistry , Topoisomerase I Inhibitors/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , DNA Topoisomerases, Type I/metabolism , Humans
6.
Chem Phys Lipids ; 164(2): 113-7, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21129369

ABSTRACT

The first total synthesis for the (Z)-16-methyl-11-heptadecenoic acid, a novel fatty acid from the sponge Dragmaxia undata, was accomplished in seven steps and in a 44% overall yield. The use of (trimethylsilyl)acetylene was key in the synthesis. Based on a previous developed strategy in our laboratory the best synthetic route towards the title compound was first acetylide coupling of (trimethylsilyl)acetylene to the long-chain protected 10-bromo-1-decanol followed by a second acetylide coupling to the short-chain 1-bromo-4-methylpentane, which resulted in higher yields. Complete spectral data is also presented for the first time for this recently discovered fatty acid and the cis double bond stereochemistry of the natural acid was established. The title compound displayed antiprotozoal activity against Leishmania donovani (IC(50) = 165.5 ± 23.4 µM) and inhibited the leishmania DNA topoisomerase IB enzyme (LdTopIB) with an IC(50) = 62.3 ± 0.7 µM.


Subject(s)
Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/pharmacology , Fatty Acids, Monounsaturated/chemical synthesis , Fatty Acids, Monounsaturated/pharmacology , Fatty Acids/chemical synthesis , Fatty Acids/pharmacology , Leishmania donovani/drug effects , Porifera/chemistry , Acetylene/chemistry , Animals , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/toxicity , Cell Line , DNA Topoisomerases, Type I/metabolism , Fatty Acids/chemistry , Fatty Acids/toxicity , Fatty Acids, Monounsaturated/chemistry , Fatty Acids, Monounsaturated/toxicity , Indicators and Reagents/chemistry , Leishmania donovani/enzymology , Macrophages/drug effects , Mice , Stereoisomerism , Topoisomerase Inhibitors/chemical synthesis , Topoisomerase Inhibitors/chemistry , Topoisomerase Inhibitors/pharmacology , Topoisomerase Inhibitors/toxicity
7.
Tetrahedron Lett ; 51(47): 6153-6155, 2010 Nov 24.
Article in English | MEDLINE | ID: mdl-21218160

ABSTRACT

The first total synthesis of the marine cyclopropane fatty acid (±)-17-methyltrans- 4,5-methyleneoctadecanoic acid was accomplished in 8 steps and in 9.1% overall yield starting from 1-bromo-12-methyltridecane. The cis analog (±)-17- methyl-cis-4,5-methyleneoctadecanoic acid was also synthesized but in 7 steps and in 16.4% overall yield. With the two isomeric cyclopropane fatty acids at hand it was possible to unequivocally corroborate the trans relative configuration of the naturally occurring fatty acid by gas chromatographic co-elution of the corresponding methyl esters. The cis isomer was cytotoxic to Leishmania donovani promastigotes with an IC(50) of 300.2 ± 4.2 µM.

8.
Chem Phys Lipids ; 161(1): 38-43, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19527698

ABSTRACT

The first total synthesis for the (Z)-17-methyl-13-octadecenoic acid was accomplished in seven steps and in a 45% overall yield. The use of (trimethylsilyl)acetylene was key in the synthesis. Based on a previous developed strategy in our laboratory the best synthetic route towards the title compound was first acetylide coupling of (trimethylsilyl)acetylene to the long-chain protected 12-bromo-1-dodecanol followed by a second acetylide coupling to the short-chain 3-methyl-1-bromobutane, which resulted in higher yields. Complete spectral data is also presented for the first time for this recently discovered fatty acid. The title compound displayed antiprotozoal activity against Leishmania donovani (EC(50) = 19.8 microg/ml) and inhibited the leishmania DNA topoisomerase IB at concentrations of 50 microM.


Subject(s)
Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Leishmania donovani/drug effects , Oleic Acids/chemistry , Oleic Acids/pharmacology , Porifera/chemistry , Animals , Antiprotozoal Agents/chemical synthesis , DNA Topoisomerases, Type I/metabolism , Leishmania donovani/enzymology , Oleic Acids/chemical synthesis
9.
Lipids ; 42(6): 519-24, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17520308

ABSTRACT

The cyclopropane fatty acids 17-methyl-trans-4,5-methyleneoctadecanoic acid, 18-methyl-trans-4,5-methylenenonadecanoic acid, and 17-methyl-trans-4,5-methylenenonadecanoic acid were characterized for the first time in nature in the phospholipids (mainly PE, PG and PS) of the hermit-crab sponge Pseudospongosorites suberitoides. Pyrrolidine derivatization was the key in identifying the position of the cyclopropyl and methyl groups in the acyl chains and (1)H NMR was used to determine the trans stereochemistry of the cyclopropane ring. The phospholipids from the sponge also contained an interesting series of iso-anteiso Delta(5,9) fatty acids with chain-lengths between 17 and 21 carbons, with the fatty acids (5Z,9Z)-18-methyl-5,9-nonadecadienoic acid and the (5Z,9Z)-17-methyl-5,9-nonadecadienoic acid being described for the first time in sponges. The anteiso alpha-methoxylated fatty acid 2-methoxy-12-methyltetradecanoic acid was also identified for the first time in nature in the phospholipids of this interesting marine sponge. The novel cyclopropyl fatty acids could have originated from the phospholipids of a cyanobacterium living in symbiosis with the sponge.


Subject(s)
Cyclopropanes/chemistry , Cyclopropanes/isolation & purification , Fatty Acids/chemistry , Fatty Acids/isolation & purification , Phospholipids/chemistry , Porifera/chemistry , Porifera/microbiology , Animals , Caribbean Region , Cyanobacteria/chemistry , Cyanobacteria/physiology , Magnetic Resonance Spectroscopy , Mass Spectrometry , Phospholipids/isolation & purification , Porifera/classification , Pyrrolidines/chemistry , Species Specificity , Stearic Acids/chemistry , Stearic Acids/isolation & purification , Symbiosis/physiology
10.
Chem Phys Lipids ; 145(1): 37-44, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17125759

ABSTRACT

The first total syntheses for the (Z)-15-methyl-10-hexadecenoic acid and the (Z)-13-methyl-8-tetradecenoic acid were accomplished in seven steps and in 31-32% overall yields. The (trimethylsilyl)acetylene was the key reagent in both syntheses. It is proposed that the best synthetic strategy towards monounsaturated iso methyl-branched fatty acids with double bonds close to the omega end of the acyl chain is first acetylide coupling of (trimethylsilyl)acetylene to a long-chain bifunctional bromoalkane followed by a second acetylide coupling to a short-chain iso bromoalkane, since higher yields are thus obtained. Spectral data is also presented for the first time for these two unusual fatty acids with potential as biomarkers and as topoisomerase I inhibitors.


Subject(s)
Fatty Acids, Monounsaturated/chemical synthesis , Myristic Acids/chemical synthesis , Palmitic Acids/chemical synthesis , Biomarkers/chemistry , Enzyme Inhibitors/chemical synthesis , Molecular Structure , Spectrum Analysis , Stereoisomerism , Topoisomerase I Inhibitors , Trimethylsilyl Compounds/chemistry
11.
J Control Release ; 89(1): 71-85, 2003 Apr 14.
Article in English | MEDLINE | ID: mdl-12695064

ABSTRACT

Protein inactivation and aggregation are serious drawbacks in the encapsulation of proteins in bioerodible polymers by water-in-oil-in-water (w/o/w) encapsulation. The model protein alpha-chymotrypsin was employed to investigate whether its stabilization towards the major stress factors in the w/o/w encapsulation procedure would allow for the encapsulation and release of non-aggregated and active protein. Due to the formation of amorphous aggregates alpha-chymotrypsin is an excellent sensor to probe unfolding events. Furthermore, its enzymatic activity is highly sensitive towards the presence of organic solvents. alpha-Chymotrypsin in aqueous solution showed substantial aggregation and activity loss when it was homogenized with CH(2)Cl(2) due to adsorption to the interface. Its w/o/w encapsulation in poly(lactic-co-glycolic)acid (PLGA) microspheres caused formation of 35% non-covalent aggregates and reduced the specific activity by 14%. Screening for efficient excipients revealed that co-dissolving the protein with maltose and polyethylene glycol (PEG, M(w) 5000) in the first aqueous phase reduced interface-induced protein aggregation and inactivation. Employing these excipients during encapsulation led to a reduction in alpha-chymotrypsin inactivation (10%) and aggregation (12%). Optimizing the effect of PEG by also dissolving the excipient in the organic phase prior to encapsulation further decreased the amount of non-covalent aggregates to 7% and loss in activity to 5%. The data obtained demonstrate that the w/o emulsification step is the main stress-factor in the w/o/w encapsulation procedure but subsequent encapsulation steps also cause some protein aggregation.


Subject(s)
Chymotrypsin/antagonists & inhibitors , Chymotrypsin/metabolism , Enzyme Stability , Methyl Chloride/chemistry , Animals , Capsules , Emulsifying Agents/chemistry , Emulsions/chemistry , Freeze Drying , Glycolates/chemistry , In Vitro Techniques , Lactic Acid , Maltose/pharmacokinetics , Methyl Chloride/pharmacokinetics , Microspheres , Polyethylene Glycols/pharmacokinetics , Polyglactin 910/chemistry , Polyglycolic Acid , Polylactic Acid-Polyglycolic Acid Copolymer , Protein Denaturation/drug effects , Serum Albumin, Bovine , Suspensions , Water
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