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"A One Pot Synthesis of Uguenenazole, a 2,5-Diaryl-1,3- Oxazole Isolated from the Roots of Vepris ugenensis (Rutaceae)**"
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Abstract The utility of oxazole as intermediates for the synthesis of new chemical entities in medicinal chemistry have been increased in the past few years. Oxazole is an important heterocyclic nucleus having a wide spectrum of biological activities which drew the attention of researchers round the globe to synthesize various oxazole derivatives and screen them for their various biological activities. The present review article aims to review the work reported on therapeutic potentials of oxazole scaffolds which are valuable for medical applications during new millennium.
From leaves and bark of Amyris pinnata Kunth twelve compounds were isolated, corresponding to six lignans 1-6, three coumarins 7-9, a sesquiterpene 10, an oxazole alkaloid 11, and a prenylated flavonoid 12,. Metabolites were identified by spectroscopic techniques (1H and 13C NMR, EIMS) and by comparison with published data in the literature. Cytotoxicity against leukemia, solid tumors, and normal cells was evaluated for all isolated compounds. Lignans were found to be the most cytotoxic compounds occurring in A. pinnata.
The reagent system of I2/K2CO3 could efficiently promote the oxazole synthesis from α-bromoketones and benzylamine derivatives in DMF. This method was not only suitable for 2,5-diaryl oxazole synthesis but also for 2,4,5-trisubstituted oxazole and 5-alkyl/alkenyl oxazole synthesis. Furthermore, this method was successfully applied to a one-step synthesis of a natural product halfordinol in 62% yield.
Texaline, an antimycobacterial oxazole-containing alkaloid previously isolated from Amyris texana and A. elemifera, and related compounds have been synthesized in order to explore aspects of the structure–antituberculosis activity relationship. While texaline was found to be inactive in our assays, simpler diaryloxazoles were more active whilst also exhibiting modest toxic selectivity, leading to their identification as potential lead compounds.
A series of diaryl- and fluorenone-based analogs of the lead compound UA-62784 [4-(5-(4-methoxyphenyl)oxazol-2-yl)-9H-fluoren-9-one] was synthesized with the intention of improving upon the selective cytotoxicity of UA-62784 against human pancreatic cancer cell lines with a deletion of the tumor suppressor gene deleted in pancreas cancer locus 4 (DPC-4, SMAD-4). Over 80 analogs were synthesized and tested for antitumor activity against pancreatic cancer (PC) cell lines (the PC series). Despite a structural relationship to UA-62784, which inhibits the mitotic kinesin centromere protein E (CENP-E), none of the analogs was selective for DPC-4-deleted pancreatic cancer cell lines. Furthermore, none of the analogs was a potent or selective inhibitor of four different mitotic kinesins (mitotic kinesin-5, CENP-E, mitotic kinesin-like protein-1, and mitotic centromere-associated kinesin). Therefore, other potential mechanisms of action were evaluated. A diaryl oxazole lead analog from this series, PC-046 [5-(4-methoxyphenyl)-2-(3-(3-methoxyphenyl)pyridin-4-yl) oxazole], was shown to potently inhibit several protein kinases that are overexpressed in human pancreatic cancers, including tyrosine receptor kinase B, interleukin-1 receptor-associated kinase-4, and proto-oncogene Pim-1. Cells exposed to PC-046 exhibit a cell cycle block in the S-phase followed by apoptotic death and necrosis. PC-046 effectively reduced MiaPaca-2 tumor growth in severe combined immunodeficiency mice by 80% compared with untreated controls. The plasma half-life was 7.5 h, and cytotoxic drug concentrations of >3 muM were achieved in vivo in mice. The diaryl oxazole series of compounds represent a new chemical class of anticancer agents that inhibit several types of cancer-relevant protein kinases.
The bark of Halfordia scleroxyla contains
the tertiary bases halfordine, C19H20O4N2
(II), halfordinone, C19H18O3N2 (III),
and halfordinol, C14H10O2N2 (IV),
together with the yellow quaternary base N-methylhalfordinium chloride, C20H23O4N2+Cl-
(I). These alkaloids are derivatives of 2(3'-pyridyl)-5-(4"-hydroxyphenyl)oxazole;
physical and chemical evidence for the structural assignments is presented.
Cytochrome P450 (CYP) enzyme inhibitory properties of six chromenylated amide compounds (CAs) from Amyris plumieri are described. Inhibition of CYP microsomes (CYP1A1, CYP1A2, CYP1B1, CYP2D6, CYP3A4 and CYP2C19) was monitored using a fluorescent assay. Potent inhibition was found against CYP1A1 with IC(50) and K(i) for CA1 (acetamide), being the lowest at 1.547 ± 1.0 μM and 0.37 μM respectively, displaying non-competitive kinetics. The selectivity for CYP1A1 was increased in CA3 (butanamide), which also exhibited cytotoxicity against breast cancer cells, MCF7 with an IC(50) of 47.46 ± 1.62 μM. Structure-activity relationship studies provide insight at a molecular level for CAs with implications in chemoprevention and chemotherapy.
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