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Naturally occurring linear fused thiazoline-thiazole containing metabolites: Total synthesis of (-)-didehydromirabazole A, a cytotoxic alkaloid from blue-green algae

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Abstract

A concise total synthesis of the thiazoline-thiazole containing metabolite didehydromirabazole A 1 is described. The synthesis uses the unusual amino acid (R)-2-methylcysteine 20 in sequential cyclocondensations with imino ethers as key steps, viz22→32 and 37→38.

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... Natural products possess the characteristics of low toxicity, good biodegradability, and compatibility, so they have been widely used as commercial fungicides (Ma et al. 2013;, insecticides (Crouse et al. 2018;Tacoli et al. 2018), and herbicides (Duke et al. 2010). In the past years, many 2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives with various biological and medicinal activities, including anti-HIV (Pattenden and Thom 1993), antibiotic (Zamri et al. 2003), and anticancer activity (Gududuru et al. 2005), have reported, whereas there is few report about the utilization in preventing plant disease. Recently, our research group have reported some (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives with amide and ester moieties, which exhibited good and broad-spectrum antifungal activities ( Fig. 1) (Liu et al. 2019(Liu et al. , 2015. ...
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To discover a novel lead structure for antiphytopathogenic fungus agent, a series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfonohydrazide moiety were designed and synthesized. They were determined by melting points, ¹H NMR, ¹³C NMR, and elemental analysis (EA). The biological activity results revealed that these title compounds possessed antifungal and insecticidal activities. Some title compounds against Alternaria solani, Physalospora piricola, Cercospora arachidicola, Phytophthora capsici, Fusarium graminearum, and Sclerotinia sclerotiorum displayed moderate to good antifungal activities at 50 mg/L, especially, compounds 6b and 6p displayed good and broad-spectrum antifungal activities. The structure activity relationships were discussed. A 3D-QSAR model was established based on the antifungal activity against Phytophthora capsici, indicating that electrostatic and hydrophobic fields were the two most significant factors for antifungal activity. Hence, structure optimization based on the CoMSIA model was performed to find compound 6p with excellent activity against Phytophthora capsici, and the EC50 values of compound 6p were comparable to those of chlorothalonil. Furthermore, the insecticidal activity of compound 6p against Culex pipiens larvae at 1 mg/L was considerable to that of chlorantraniliprole. Therefore, compound 6p can be used as a novel lead structure for antiphytopathogenic fungus and insecticidal agent development.
... (R)-2-(2-Hydroxyphenyl)-4,5-dihydrothiazole-4-carboxylic acid, as a natural product representative of 2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives, has been confirmed to possess anticancer activity for L1210 cell lines in vitro [12]. In the past years, researchers have reported many 2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives with a variety of biological activities in medicinal chemistry, including antibiotic [13], anti-HIV [14], and anticancer activities [15]. However, few researches about the application in plant disease prevention have been reported. ...
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Total Synthesis of antibiotic althiomycin has been achieved starting from D-cysteine. The imide bond between thiazoline and the pyrrolinone part was constructed by coupling reaction of sodium salt of pyrrolinone with cysteine active ester or by photoreaction with diketene. The hydroxymethyl group attached on the carbon adjacent to C-2 of the thiazoline ring, was introduced by aldol condensation posterior to the thiazoline ring formation. The thiazole part was introduced in a final step in whole process of the total synthesis of the antibiotic. The synthetic althiomycin was identical with the natural antibiotic in all respects.
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A protected heptapeptide, the formyl-L-isoleucyl-ε-benzyloxycarbonyl-L-lysyl-δ-5-tosyl-D-ornithyl-L-isoleucyl-D-phenylalanyl-im-benzyl-L-histidyl-L-aspartic acid α-methyl-β-benzyl ester, was synthesized by the azide method and the carbodiimide method. It is an intermediate peptide for the total synthesis of the antibiotic bacitracin A, the structure of which is still ambiguous at a few points. β-Benzyl benzyloxycarbonyl-L-aspartate was prepared by a novel method similar to that used in the synthesis of γ-benzyl glutamate. The α-methyl-β-benzyl L-aspartate prepared could be useful in the synthesis of branched aspartic acid peptide. Phenomena of dimorphism were observed in crystals of δ-tosyl-D-ornithine and δ-tosyl-D-ornithyl-L-isoleucyl-D-phenylalanine ethyl ester hydrobromide, and two crystal forms of each compound were isolated in pure states.
Article
Mirabimide A, the major imide from the terrestrial blue-green alga Scytonema mirabile (Dillwyn) Bornet (strain BY-8-1), is N-[2-(N,N-dimethylleucyl)oxy-3-methylpentanoyl-N-methylvalyl-prolyl]-4-methoxy-5-isopropyl-3-pyrrolin-2-one. Mirabimides B–D are the valyl, 2-oxy-3-methylbutanoyl, and N-acetyl-N-methylleucyl analogs, respectively. The absolute configurations of the five asymmetric carbons in the mirabimides are proposed to be all S, but the assignments for the dimethylleucine units in A–C and the hydroxyacid units in B–D are tentative.
Article
Using a biological screening with a HIV-1/MT-4 cell assay indicating antiviral activity and cell toxicity, we detected and isolated a new inhibiting metabolite from gliding bacteria, thiangazole (1). The structure of 1 was determined by spectroscopic methods to be a tris(thiazoline) derivative, showing a remarkable similarity to tantazole B (2). Chemical degradation and comparison with a synthetically prepared reference compound as well as with the degradation product from 2 furnished the (5R,8S,11S) configuration of the asymmetric centers in 1.
Article
A concise total synthesis of the thiazole-thiazoline based metabolite (-)-didehydromirabazole A (2), a cytotoxic alkaloid isolated recently from the blue-green alga Scytonema mirabile, is described which uses sequential cyclocondensation reactions with methyl (R)-2-methylcysteine hydrochloride (5) as key steps, viz6 → 7 and 10 → 11.
Article
Certain thiazoles are obtained via dehydrative cyclization of the corresponding cysteinyl peptides and oxidation of the resulting thiazolines with NiO2; the biomimetic syntheses of two natural products are reported, as is the potential of NiO2 as an oxidant for other partially reduced heterocycles.
Article
The lipophilic extract of the cultured terrestrial blue-green alga Scytonema pseudohofmanni Bharadwaja contains five novel macrolides, scytophycins A (1), B (2), C (3), D (4), and E (5), which exhibit cytotoxicity and antifungal activity. The structures of 1-5 have been determined mainly from spectroscopic data. The relative stereochemistries of the scytophycins are based on an X-ray crystallographic analysis of a transformation product of scytophycin C (8) and comparison of the 1H and 13C NMR spectra of 1-5. The absolute stereochemistries of the scytophycins have been deduced from a circular dichroism study of the dibenzoate ester 16, obtained in five steps from scytophycin B, and comparison of the CD curves of 1-5. These novel secondary metabolites appear to be biogenetically related to the marine natural products swinholide A, ulapualides A and B, and kabiramide C.
Article
An aerial form of Scytonema mirabile (Dillwyn) Bornet, designated strain number BY-8-1, has been found to contain six novel isonitriles, viz. mirabilene isonitriles A-P (7-12), which are mildly cytotoxic and antimicrobial. The gross structures of 7-12 were determined by detailed spectral analysis. The relative and absolute stereochemistry of 7-12 were solved by chemical degradation and direct comparison of degradation products with synthetic samples; mirabilene-A isonitrile (7), for example, was degraded to methyl (3R,5R,7S,9S)-3,5,7,9-tetramethoxy-10-oxoundecanal (15) and isopropyl (S)-3-trifluoroacetamidobutyrate (14), which indicated that the absolute configurations of C-4, C-6, C-8, C-10, and C-16 in 7 were all S.
Article
The tetrathiazoline marine alkaloid (-)-mirabazole C (7) has been synthesized by cyclization of a diamide derivative of the tripeptide derived from (R)-2-methylcysteine.
Article
Treatment of the N-formyl derivative of the thiazolidine adduct derived from (R-cysteine methyl ester hydrochloride and pivalaldehyde, with LDA-DMPU at −90°C, followed by reaction with iodomethane produces the corresponding methylated thiazolidine containing the methyl and t-butyl groups virtually exclusively anti- to one another. Hydrolysis in the presence of 5M HCl then affords (R-2-methylcysteine hydrochloride in excellent yield and enantiomeric purity. A range of other 2-alkyl substituted cysteines of excellent optical purity are prepared by this modification of Seebach's “self-reproduction of chirality” protocol.
Article
Anguibactin (1), a novel siderophore isolated from the fish pathogen Vibrio anguillarum 775 (pJM1), has been identified as ω-N-hydroxy-ω-N-[[2′-(2″,3″-dihydroxyphenyl) thiazolin-4′-yl]carboxy]histamine. The structure determination was based on (i) single-crystal X-ray diffraction studies of its anhydro derivative (2), (ii) 1H and 13C NMR spectroscopy, (iii) FAB mass spectrometry, and (iv) chemical degradation. Anhydroanguibactin (2) crystallizes in the monoclinic space group C2/c, a = 22.71 (5) Å, b = 8.052 (6) Å, c = 15.879 (18) Å, β = 95.72 (9)°, V = 2889.2 Å3, and Z = 8. The structure has been determined from 2029 diffractometer data and refined to a final R = 0.048. Spectroscopic results have shown that anguibactin (1) differs from 2 by having (i) a thiazoline ring instead of a thiazole ring and (ii) a hydroxyl group on the peptide N atom of the histamine residue. Anguibactin belongs to a unique structural class of its own, with its backbone derived from ω-N-hydroxyhistamine, cysteine, and 2,3-dihydroxybenzoic acid. The structure of another related compound, copurified with anguibactin, was identified as 2-(2′,3′-dihydroxyphenyl)thiazoline-4-carboxylic acid methyl ester (3).
Article
An iron-binding compound was isolated from ethyl acetate extracts of culture supernatant fluids of Pseudomonas aeruginosa and was purified by successive paper and thin-layer chromatographic procedures. The purified compound was characterized by UV, visible, infrared, and fluorescence spectroscopy. The compound possesses phenolic characteristics, with little or no similarity to dihydroxybenzoates and no indication of a hydroxamate group. P. aeruginosa synthesized the compound during active growth in culture media containing less than 5 X 10(-6) M added FeCl3. When added to iron-poor cultures of P. aeruginosa, the compound promoted the growth of the bacterium and also reversed growth inhibition by the iron chelator ethylenediamine-di-(o-hydroxyphenylacetic acid).
Article
Aus dem leicht synthetisierbaren Thiazolin (Ia) sind die Amide (Ib) bzw. (Ic) zugänglich, die sich über die (zweckmäßig nicht isolierten) Bromide (IIa) bzw. (IIb) (jeweils Isomerengemische) zu den β-Lactam-thiazolinen (IIIa) bzw. (IIIb) cyclisieren lassen.
Article
Tolytoxin [1], the major cytotoxin associated with Scytonema mirabile strain BY-8-1, Scytonema burmanicum strain DO-4-1 and Scytonema ocellatum strains DD-8-1, FF-65-1, and FF-66-3, has been shown to be 6-hydroxy-7-O-methylscytophycin B. Minor amounts of three other new cytotoxic scytophycins, 6-hydroxyscytophycin B [2], 19-O-demethylscytophycin C [3], and 6-hydroxy-7-O-methylscytophycin E [4], have also been isolated from these cyanophytes. The gross structures and stereochemistry are based on nmr and cd analysis and on comparison with scytophycins A-E.
Article
The isolation and structures of a new patellamide (patellamide D) and two new lissoclinamides (lissoclinamides 4 and 5) from the aplousobranch ascidian Lissoclinum patella are described. Structures were determined largely by using two-dimensional NMR techniques and mass spectrometry. These peptides and other members of the patellamide and lissoclinamide families that have been reported previously are found within the obligate algal symbiont of the genus Prochloron. The cytotoxicities of the compounds toward fibroblast and tumor cell lines are reported. One of these compounds, lissoclinamide 4, is markedly more toxic than other members of the family. Structure-activity relationships are discussed.
Article
The hydrolysis of 13 Δ2-thiazolines has been investigated in the pH range 0-6 at 30°. Analysis of the characteristic, bell-shaped rate-pH profiles as well as the effect of variation in the polar nature of aryl substituents in the 2-position of the thiazoline nucleus support the general validity of a previously proposed mechanism for thiazoline hydrolysis. The rate of hydration of thiazolines has been found to vary by a factor of 38,000 over the series of compounds examined. For ten 2-arylthiazolines, with or without 4-substitution, a linear relationship between the logarithm of the hydrolysis rate constant and the pK of the thiazolinium ion has been noted. A parallel relationship appears valid for 2-melhylthiazolines, which are about 250 times more reactive than 2-arylthiazolines of the same pK. The observation of a constant rate of hydrolysis of 2-methylthiazoline at alkaline pH (78°) is discussed.
  • Inami
  • Jeanguenat
  • Linderstrøm-Lang