Marine-derived 1,3-Oxazole-Containing Alkaloids

Marine-derived 1,3-Oxazole-Containing Alkaloids: Comparison

Please note this is a comparison between Version 2 by Camila Xu and Version 1 by Huawei Zhang.

1,3-Oxazole compounds are a unique class of five-membered monocyclic heteroarenes, containing a nitrogen atom and an oxygen. These alkaloids have attracted extensive attention from medicinal chemists and pharmacologists owing to their diverse arrays of chemical structures and biological activities, and a series of 1,3-oxazole derivatives has been developed into therapeutic agents, such as almoxatone, befloxatone, cabotegravir, delpazolid, fenpipalone, haloxazolam, inavolisib.

oxazole
alkaloid
marine natural product
bioactive property
marine organism
marine sponge
symbiotic microorganism

1. BPenzoxazolptides

ChTwo novemical study of a halophilic strain Nocardiopsis lucentensis DSM 44048 yielded seven new benzoxazoles, nocarbenzoxazoles A–Gl linear and achiral polyketide-peptides, ariakemicins A (18) 264–and 270)B ( Scheme 17 19), in which 270 had selective activity against HepG2 and HeLa cell lines with a IC 50 of 3 and 1 μM, respectively [147].Oere obtained as an inseparable mixture from one 6-methoxy-2(3 H )-benzoxazolinone, coixol ( 271), was detected in the DCM-MeOH extract of the marinearine gliding bacterium spongeRapidithrix Oceanapia sp., collected off Mandapam coast (India), and had extensive bioactivities, including an inhibitory effect on brine shrimp, anti-inflammation and anti-diabetes [149].Compouthe muddy land alongside the Ariake Inland Sea, and displayed selectively antimicrobial activities againds 272 and 273 were chemically synthesized by a rat Gram-positive bacteria (Brevibacterium spid., S. aureus, oane-pot method [153]Bacillus subtilis), and thwe total synthesis of 275 was accomplished using a new enantioselective approachak cytotoxicity against cancer cell lines A549 and BHK [154 25]. Benzoxazole-containing compoundsreitfussins A–H (20–27) awere one important class of the first marine natural products with a potential application in pharmaceutical and agrochemical fields [140,141].

One new benzcontaining an indole-oxazole-pyrrole caboxamycin ( 281), from the deep-sea straiframework from hydrozoan StreptomycesThuiaria breitfussi sp.Two inovel anti-MRSA xanthones, citreamicins θA ( 283) and θB ( 284), were separated from one marine-derived strain of Streptomyces caelestis [162].Hamhabits in the Arctic ocean, and were found to excellently igeran M ( 282) was the first non-benzo-fused oxazole-containinghibit PIM1 and DRAK1 kinases [26,27]. Furterpenoid from the New Zealand marine sponge Hamigerahermore, breitfussin C (22) starangaensis , and rongly exhibited the high efficacy against the HL-60 promyelocytic leukemia a cytotoxic effect on cancer cell line with a mean IC 50 value of 6.9 ± 0.4 μM [161].from s (MCF-7, HT-29, MOLT-4, MV-4-11 a marine sediment resulted in the production of herqueioxazole (278), which was the first oxazole-containing phenalenone [156].

2. Polyketides

Bd MRC-5). One concise total sy OSMAC (one strain many compounds) strategy, inthomycin B ( 217) was produced by the marine sediment-derived Streptomycthesis of the halogen-rich dipeptides YB10420 and 21 was founcreated to have anti-oomycete, cytotoxic and herbicidal activities [132].Andby Bayer and his coworkers in 2015, which consists of the gene cpalluster ( itm ) responsible for biosynthesis of 217 was identified as a 95.3 kb trans-AT type I PKS system, of which the gene Itm 15 is a cyclodehydrase to catalyze the formadium-catalyzed cross-coupling of indole and pyrrole on an oxazole core and selective lithiation/iodination of oa common indole-oxazole ringfragment [132 28]C. Mecherchalyculinsrmycin B (28) 198–was 216) ( Scheme 15 ) were novel polyketidesa new linear peptide containing a monofour 1,3-oxazole and a phosphate group fromrings produced by the marine sponges Discodermiatrain calyxThermoactinomyces , Lamellomorspha strongylat , Luffariella geometrica , Myriastra clavosa and. YM3-251 from Mecherchar (Palau) [29]. TSipheonella swinhoei .Theseonazole (29) anatural products exhibited extensive biologicald dimethoxy analog (30) pweroperties including cytotoxicity, antifungal activity and an inhibitory effect on protein phosphatases [126,127,128,129,130,131].

Bye the first naturally occurring substances that exteinsive chromatographic techniques, eight henncorporated oxazoles ( 222– 229) were isolated from the sponge Polyfibrospongia sp., of which 222 had peripheral analgesic activity equivalent to the positive control subunits connected by a two-carbon tether from a marine microbe ofHerpetosiphon indomethacinsp., and 228 exhibited the greatestselective cytotoxicity toward L1210 with an IC 50 value of 2 µg/mL [135,136].An uncommo human oxazole, bengazole A ( 237) from the sponge Jaspis sp., displayed remarkable ergosterol-dependent antifungal activity against C. albicans ,reast cancer HTB-129 and acute T cell leukemia TIB-152 [30]. wThich is equivalent to amphotericin B [139]Four analoge first chemical synthesis of the29 trioxwazole macrolide 169 linked with a methyl ester and a primary amide group, secohalichondramide ( 218) ( Scheme 16 ), halishigamides C ( 219) and D ( 220), and kabiramide H ( 221), were isolated from marine sponges, including Chondrosia corticate , Halichondria sp.Metabolites 219 and 220 showed weak cytotoxicity against L1210 and KB cell lines and a modest antifungal activity against T. mentagrophytes s achieved in 2007 through the preparation of an oxazole ring using rhodium carbene, and the installation of the pentadienyl amino side-chain [111 31].

32. Macrolides

Two cytotoxic isomers, phorboxazoles A ( 138138) ( Scheme 10 Scheme 10) and B ( 139139), as well as the precursor ( 140140) were detected in the Indian Ocean marine sponge Phorbas sp. [102,103]. Leiodolides A (141) and B P(142) were the first members orbas spf a new class of mixed polyketide-nonribosomal peptide synthetase from the deep-water marine sponge Leiodermatium. They structurally possess a 19-membered ring and several unique functional groups, including a bromine substituent and an α-hydroxy-α-methyl carboxylic acid side-chain terminus.Leiodolides A ( 141) and B ( 142) were th These substances had obvious cytotoxic effects against human colon cancer HCT-116 with IC₅₀ values first mof 2.5 and 5.6 μM, respectively [104]. Chembical invers of a newstigation of the Madagascan sponge Fascaplysinopsis class of mixed polyketide-nonribosomal peptide syntp. afforded three macrolides with bis-epoxide motif salarins 143–145, whicheta se from the deep-water marinehowed pronounced inhibitory on human leukemia cell lines UT-7 [105,106]. spTheonge Leiodeezolides A–C (146–148) fromatium the Okinawan Theonella sp. were novel oxazole-containing macrolides that compose of two main fatty acid chains, including a 37-membered macrolide ring with long side chains connected by amide bonds.

Mycalolides A–C ( 159– 161) ( ScTheme 13 ) and their derivatives ( 162– 165, 176, 177, 179) were obtained from a marine sponge of the genus Mycale, except mycalolide E ( 166) from the coral Tubastrea faulkneri , of which 176 and 177 possessed one sulfur atom connected to the glutathionyl group (i-Glu-Cys-Gly) at C-5 [116].Phytoy exhibited cytotoxicity on a murine lymphoma L1210 and human epidermoid carcinoma KB chemical analysis of sponges Halichondria sp.Kabiramides ( 180– 182, 185– 192) were discovered in the Hexabranchus egg masses and the sponge Pachastrissa nux, and displayed extraordinary cytotoxicities, and antiplasmodial and antifungal activities [119]Bioassay lls and induced a platelet morphology change and aggregation in revealed that these substances exhibited excellent cytotoxicitiebbits [117 107,108,109].

43. Pepolyketides

TwBy OSMAC (o novel linear and achiral polyketide-peptides, ariakemicins A ( 18) and ne strain many compounds) strategy, inthomycin B ( 19217) , were obtained as an inseparable mixture from onas produced by the marine gliding bacterium Rapidithrix sp., collectesediment-derived offStreptomyces theYB104 muddy land alongside the Ariake Inland Sea, and displayed selectively antimicrobiand was found to have anti-oomycete, cytotoxic and herbicidal activities [132]. agaiOnst Gram-positive bacteria ( Brevibacterium sp., S. aureus , and Bacillus subtilise concise method to synthesize ), and217 weak cytotoxicity against cancer cell lines A549 and BHK [25].Siphs developed by Webb and conazwole ( 29) and dimethoxy analog ( 30) were the first naturally occurring substances that incorporatedrkers through the Stille coupling of a stannyl-diene with an oxazole subunits connected by a two-carbon tether from a marine microbe Herpetosiphon sp., and exhibited selective cytotoxicity to human breast cancer HTB-129 and acute T cell leukemia TIB-152 [30].Mvinyl iodide unit and a Kiyooka ketene acetal/amino acid-dechercharmycin B ( 28) was a new linear peptide containing four 1,3-oxazole rings proived oxazaborolidine procedure as its cornerstones [133]. Anduced by the marine straingene cluster (itm) Thrermoactinomyces sp.The first chemical sponsible for biosynthesis of 29217 was achieved in 2007 through the preparation of an oxazole ring using rhodium carbene, and the installation of the pentadienyldentified as a 95.3 kb trans-AT type I PKS system, of which the gene Itm15 amino side-chain [31]

Tots al synthesis study indicated that macrocyclization initiated by the thermal rearrangement of β -keto tert -butcyclodehydrase to catalyze the formation of oxazole ring [132].

Byl ester yielded 21% of 133 ( Scheme 9 ) and determined the configuration of C-9 as S [100].Four cyclic dxtensive chromatographic techniques, epsipeptides, discokiolides A–D ght hennoxazoles ( 134222– 137229), were characterizeisolated from the marine sponge DiscodermiaPolyfibrospongia kiiensis and exhibitedp., of which a222 brohad spectrum of cytotoxic activities against P388, P388/ADM, B16-BL6, Lewis, Lu-99, HT-29 and CCD-19Lu with IC 50 values ranged from 0.5 to 7.2 μg/mL [101]and found peripheral analgesic acto inhibit the growth of the human UT-7 leukemic cell line at 1 µM [99].Taumycin A ( 133) was obvity equivalent tained from the Madagascan sponge Fascaplysinopsis sp.

5. Conclusions

Many importan the posit marine-derived 1,3-oxazoles have great potential for the development of leading compounds in the search for new drugs ve control of indomethacin, and m228 edxhicines.These substances possess unique chemical structures and exhibit a wide variety of biological properties.For example, mechercharmycin A ( 119) is a promisingbited the greatest cytotoxicity toward L1210 with an IC₅₀ vantitumor remedy, and (19Z)-halichondramide ( 168)lue of 2 µg/mL [135,136]. Aneohalichondramide ( 175), and calyculin A–D ( 190, 200– 202tibiotic B-90063 (230) hwave the potential to treat human leukemia cell line.However, (1) how to reduce cytotoxicity, (2) how to improve drug stability, and (3) how to make the drug work quickly and effectively is a novel endothelin-converting enzyme (ECE) inhibitor from the marine strain vivoBlastobacter stillp. SANK needs to be studied in further depth

In re71894, collected off the cent yeoars, however, the number of new 1,3-oxazole derivatives from marine organisms has greatlyst of Ojika Peninsula [137]. decrBeased, since almost all accessiblengazoles macroorganisms231–236 havwe been collected and chemically analyzed.In order to discover novel marine microbe-derived 1,3-oxazoles for new drug discovery, more efforts should be made to conduct strain isolation and chemicalre antifungal agents obtained from the marine sponge studyPachastrissa using a combination of classical methods (e.g., cultivation and fermentation, bioassay-guided fractionation, structure elucidation) ap., collected at Musha Archipelago (Djibouti) [138]. And advanced analytical techniques (e.g., metabolomics, higher-field NMR instruments,uncommon oxazole, bengazole A (237) pfrobe technology), genome miningm the sponge andJaspis engineeringsp., and microbial cultivating systems (e.g., OSMAC approach) [168]. Simudisplayed remarkabltaneously, marine microorganisms are shown to be one prolific and unexploited source of bioactive natural ergosterol-dependent antifungal activity against productsC. albicans, owing to their species richness and abundant secondary metabolite BGCs, especially symbiotic microbes of marine sponges, seaweeds, mangroves and tunicates hich is equivalent to amphotericin B [164,165,166,167 139].

4. Benzoxazoles

Chemical study of a halophilic strain Nocardiopsis lucentensis DSM 44048 yielded seven new benzoxazoles, nocarbenzoxazoles A–G (264–270) (Scheme 17), in which 270 had selective activity against HepG2 and HeLa cell lines with a IC₅₀ of 3 and 1 μM, respectively [147]. Recently, a simple route to the synthesis of 269 and 270 was achieved by microwave-assisted construction of a benzoxazole skeleton [148]. One 6-methoxy-2(3H)-benzoxazolinone, coixol (271), was detected in the DCM-MeOH extract of the marine sponge Oceanapia sp., collected off Mandapam coast (India), and had extensive bioactivities, including an inhibitory effect on brine shrimp, anti-inflammation and anti-diabetes [149]. Bioassay-guided fractionation of an extract from the sea plum Pseudopterogorgia elisabethae led to the isolation of homopseudopteroxazole (272), pseudopteroxazole (273), seco-pseudopteroxazole (274) and ileabethoxazole (275) [150,151]. Oxazocurcuphenol (276) was isolated and characterized from the coral P. rigida, collected at Lighthouse Point on the Eleuthera island (Nassau, Bahamas) [152]. Biological tests suggested that 272 and 273–275 strongly inhibited the growth of Mycobacterium tuberculosis H₃₇R0v at 12.5 µg/mL. Compounds 272 and 273 were chemically synthesized by a rapid one-pot method [153], and the total synthesis of 275 was accomplished using a new enantioselective approach [154].

Scheme 17. Marine-derived benzoxazoles (254–285).

To the best of our knowledge, citharoxazole (277) was the first chlorinated oxazole-containing pyrrolo[4,3,2-de]quinoline from the Mediterranean deep-sea sponge Latrunculia (Biannulata) citharistae [155]. Culture of the marine fungus Penicillium sp. from a marine sediment resulted in the production of herqueioxazole (278), which was the first oxazole-containing phenalenone [156].

5. Conclusions

In recent decades, a tremendous number of 1,3-oxazole-containing alkaloids have been isolated and characterized from marine organisms, including marine invertebrates, nematodes, insects, vertebrates cyanobacteria, bacteria, and fungi. These substances possess unique chemical structures and exhibit a wide variety of biological properties. Many important marine-derived 1,3-oxazoles have great potential for the development of leading compounds in the search for new drugs and medicines. For example, mechercharmycin A (119) is a promising antitumor remedy, and (19Z)-halichondramide (168), neohalichondramide (175), and calyculin A–D (190, 200–202) have the potential to treat human leukemia cell line. Besides, plenty of these substances are potential antimicrobial agents, such as kocurin (118), TP-1161 (121) homopseudopteroxazole (272), and so on. However, (1) how to reduce cytotoxicity, (2) how to improve drug stability, and (3) how to make the drug work quickly and effectively in vivo still needs to be studied in further depth.

In recent years, however, the number of new 1,3-oxazole derivatives from marine organisms has greatly decreased, since almost all accessible macroorganisms have been collected and chemically analyzed. Simultaneously, marine microorganisms are shown to be one prolific and unexploited source of bioactive natural products, owing to their species richness and abundant secondary metabolite BGCs, especially symbiotic microbes of marine sponges, seaweeds, mangroves and tunicates [164,165,166,167]. In order to discover novel marine microbe-derived 1,3-oxazoles for new drug discovery, more efforts should be made to conduct strain isolation and chemical study using a combination of classical methods (e.g., cultivation and fermentation, bioassay-guided fractionation, structure elucidation) and advanced analytical techniques (e.g., metabolomics, higher-field NMR instruments, probe technology), genome mining and engineering and microbial cultivating systems (e.g., OSMAC approach) [168].