1. 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 IC 50 of 3 and 1 μM, respectively [147].One 6-methoxy-2(3 H )-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].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]Benzoxazole-containing compounds are one important class of natural products with a potential application in pharmaceutical and agrochemical fields [140,141].

One new benzoxazole caboxamycin ( 281), from the deep-sea strain Streptomyces sp.Two novel anti-MRSA xanthones, citreamicins θA ( 283) and θB ( 284), were separated from one marine-derived strain of Streptomyces caelestis [162].Hamigeran M ( 282) was the first non-benzo-fused oxazole-containing terpenoid from the New Zealand marine sponge Hamigera tarangaensis , and exhibited the high efficacy against the HL-60 promyelocytic leukemia cell line with a mean IC 50 value of 6.9 ± 0.4 μM [161].from a marine sediment resulted in the production of herqueioxazole (278), which was the first oxazole-containing phenalenone [156].

2. Polyketides

By OSMAC (one strain many compounds) strategy, inthomycin B ( 217) was produced by the marine sediment-derived Streptomyces YB104 and was found to have anti-oomycete, cytotoxic and herbicidal activities [132].And the gene cluster ( 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 formation of oxazole ring [132]Calyculins ( 198– 216) ( Scheme 15 ) were novel polyketides containing a mono-oxazole and a phosphate group from the marine sponges Discodermia calyx , Lamellomorpha strongylat , Luffariella geometrica , Myriastra clavosa and Theonella swinhoei .These natural products exhibited extensive biological properties including cytotoxicity, antifungal activity and an inhibitory effect on protein phosphatases [126,127,128,129,130,131].

By extensive chromatographic techniques, eight hennoxazoles ( 222– 229) were isolated from the sponge Polyfibrospongia sp., of which 222 had peripheral analgesic activity equivalent to the positive control of indomethacin, and 228 exhibited the greatest cytotoxicity toward L1210 with an IC 50 value of 2 µg/mL [135,136].An uncommon oxazole, bengazole A ( 237) from the sponge Jaspis sp., displayed remarkable ergosterol-dependent antifungal activity against C. albicans , which is equivalent to amphotericin B [139]Four analogs of the trioxazole 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 [111].

3. Macrolides

Two cytotoxic isomers, phorboxazoles A ( 138) ( Scheme 10 ) and B ( 139), as well as the precursor ( 140) were detected in the Indian Ocean marine sponge Phorbas sp.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 the first members of a new class of mixed polyketide-nonribosomal peptide synthetase from the deep-water marine sponge Leiodermatium .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) ( Scheme 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].Phytochemical 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 revealed that these substances exhibited excellent cytotoxicities [117].

4. Peptides

Two novel linear and achiral polyketide-peptides, ariakemicins A ( 18) and B ( 19) , were obtained as an inseparable mixture from one marine gliding bacterium Rapidithrix sp., collected off the muddy land alongside the Ariake Inland Sea, and displayed selectively antimicrobial activities against Gram-positive bacteria ( Brevibacterium sp., S. aureus , and Bacillus subtilis ), and weak cytotoxicity against cancer cell lines A549 and BHK [25].Siphonazole ( 29) and dimethoxy analog ( 30) were the first naturally occurring substances that incorporated 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].Mechercharmycin B ( 28) was a new linear peptide containing four 1,3-oxazole rings produced by the marine strain Thermoactinomyces sp.The first chemical synthesis of 29 was achieved in 2007 through the preparation of an oxazole ring using rhodium carbene, and the installation of the pentadienyl amino side-chain [31]

Total synthesis study indicated that macrocyclization initiated by the thermal rearrangement of β -keto tert -butyl ester yielded 21% of 133 ( Scheme 9 ) and determined the configuration of C-9 as S [100].Four cyclic depsipeptides, discokiolides A–D ( 134– 137), were characterized from the marine sponge Discodermia kiiensis and exhibited a broad 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 to inhibit the growth of the human UT-7 leukemic cell line at 1 µM [99].Taumycin A ( 133) was obtained from the Madagascan sponge Fascaplysinopsis sp.

5. Conclusions

Many important marine-derived 1,3-oxazoles have great potential for the development of leading compounds in the search for new drugs and medicines.These substances possess unique chemical structures and exhibit a wide variety of biological properties.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.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.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]. 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].

This entry is adapted from the peer-reviewed paper 10.3390/ph14121274