120-08-1Relevant articles and documents
Lamellarins as inhibitors of P-glycoprotein-mediated multidrug resistance in a human colon cancer cell line
Plisson, Fabien,Huang, Xiao-Cong,Zhang, Hua,Khalil, Zeinab,Capon, Robert J.
, p. 1616 - 1623 (2012)
Chemical analysis of a Didemnum sp. (CMB-01656) collected during scientific Scuba operations off Wasp Island, New South Wales, yielded five new lamellarins A1 (1), A2 (2), A3 (3), A4 (4) and A5 (5) and eight known lamellarins C (6), E (7), K (8), M (9), S (10), T (11), X (12) and χ (13). Analysis of a second Didemnum sp. (CMB-02127) collected during scientific trawling operations along the Northern Rottnest Shelf, Western Australia, yielded the new lamellarin A6 (14) and two known lamellarins G (15) and Z (16). Structures were assigned to 1-16 on the basis of detailed spectroscopic analysis with comparison to literature data and authentic samples. Access to this unique library of natural lamellarins (1-16) provided a rare opportunity for structure-activity relationship (SAR) investigations, probing interactions between lamellarins and the ABC transporter efflux pump P-glycoprotein (P-gp) with a view to reversing multidrug resistance in a human colon cancer cell line (SW620 Ad300). These SAR studies, which were expanded to include the permethylated lamellarin derivative (17) and a series of lamellarin-inspired synthetic coumarins (19-24) and isoquinolines (25-26), successfully revealed 17 as a promising new non-cytotoxic P-gp inhibitor pharmacophore. Copyright
Synthesis and structure-activity relationship of coumarins as potent Mcl-1 inhibitors for cancer treatment
Xia, Yang-Liu,Wang, Jing-Jing,Li, Shi-Yang,Liu, Yong,Gonzalez, Frank J.,Wang, Ping,Ge, Guang-Bo
, (2021)
Myeloid cell leukemia-1 (Mcl-1) is a validated and attractive target for cancer therapy. Over-expression of Mcl-1 in many cancers allows cancer cells to evade apoptosis and contributes to their resistance to current chemotherapeutics. In this study, more than thirty coumarin derivatives with different substituents were designed and synthesized, and their Mcl-1 inhibitory activities evaluated using a fluorescence polarization-based binding assay. The results showed that the catechol group was a key constituent for Mcl-1 inhibitory activity of the coumarins, and methylation of the catechol group led to decreased inhibitory activity. The introduction of a hydrophobic electron-withdrawing group at the C-4 position of 6,7-dihydroxycoumarin, enhanced Mcl-1 inhibitory capacity, and a hydrophilic group in this position was unbeneficial to the inhibitory potency. In addition, the introduction of a nitrogen-containing group to the C-5 or C-8 position, which allowed an intramolecular hydrogen bond, was also unfavorable for Mcl-1 inhibition. Among all coumarins tested, 4-trifluoromethyl-6,7-dihydroxycoumarin (Cpd 4) displayed the most potent inhibitory activity towards Mcl-1 (Ki = 0.21 ± 0.02 μM, IC50 = 1.21 ± 0.56 μM, respectively), for which the beneficial effect on taxol resistance was also validated in A549 cells. A strong interaction between Cpd 4 and Mcl-1 in docking simulations further supported the observed potent Mcl-1 inhibition ability of Cpd 4. 3D-QSAR analysis of all tested coumarin derivatives further provides new insights into the relationships linking the inhibitory effects on Mcl-1 and the steric-electrostatic properties of coumarins. These findings could be of great value for medicinal chemists for the design and development of more potent Mcl-1 inhibitors for biomedical applications.
Psoralen and coumarin photochemistry in HSA complexes and DMPC vesicles
Chen,Rinco,Popov,Vuong,Johnston, Linda J.
, p. 31 - 37 (2006)
The photochemistry and photophysics of several psoralens and coumarins have been examined in human serum albumin (HSA) complexes and dimyristoylphosphatidylcholine (DMPC) vesicles. Fluorescence spectroscopy indicates that there are multiple binding sites with polarities that are intermediate between those of acetonitrile and water for the substrates complexed to HSA. In the case of the 6,7-dimethoxycoumarin-HSA complex, laser flash photolysis experiments provide evidence for the formation of radical cation in addition to triplet. Radical cations are not detected for other coumarin-HSA complexes, either due to a lower yield of formation or to rapid reaction of an initial radical cation with adjacent amino acids. Fluorescence spectra for coumarins indicate that they are primarily solubilized in the polar headgroup region in DMPC vesicles. Consistent with this, radical cations generated by photoionization are detected in transient experiments. For dimethoxycoumarins the radical cation is long-lived, indicating rapid exit from the vesicle and decay in the aqueous phase. However, 4,5′,8- trimethylpsoralen and 7-ethoxy-4-hexadecylcoumarin radical cations are much shorter-lived, presumably due to rapid decay by electron recombination in the vesicle. The results for both HSA complexes and vesicles indicate that radical ions may play a role in psoralen and coumarin photochemistry in a cellular environment.
Design, Synthesis, and Characterization of Small-Molecule Reagents That Cooperatively Provide Dual Readouts for Triaging and, When Necessary, Quantifying Point-of-Need Enzyme Assays
Brooks, Adam D.,Mohapatra, Hemakesh,Phillips, Scott T.
, p. 10437 - 10445 (2015)
A newly designed small molecule reagent provides both qualitative and quantitative readouts in assays that detect enzyme biomarkers. The qualitative readout enables rapid triaging of samples so that only samples that contain relevant concentrations of the target analyte must be quantified. The reagent is accessible in essentially three steps and 34% overall yield, is stable as a solid when heated to 44 °C for >1 month, and does not produce background signal when used in an assay. This paper describes the design and synthesis of the reagent, characterizes its response properties, and establishes the scope of its reactivity.
Cascade synthesis of 3-alkenylcoumarins by palladium-catalyzed reaction of phenols and ethyl propiolate
Kitamura, Tsugio,Tatemoto, Kotaro,Sakai, Mariko,Oyamada, Juzo
, p. 705 - 707 (2012)
A highly effective cascade process giving 3-alkenylcoumarins is furnished by a series of reactions involving palladaarylation of ethyl propiolate with phenols, intramolecular transesterification to 3-coumarylpalladium species, its alkyne insertion, and protonation. [Pd(OAc)2(dppe)] is an effective catalyst for the synthesis of 3-alkenylcoumarins from phenols and ethyl propiolate.
A Convenient Synthesis of a Simple Coumarin from Salicylaldehyde and Wittig Reagent (I): A Synthesis of Methoxy- and Hydroxycoumarins
Harayama, Takashi,Katsuno, Keiko,Nishioka, Hiromi,Fujii, Masako,Nishita, Yoshitaka,et al.
, p. 613 - 622 (1994)
Reaction of methoxy- and hydroxysalicylaldehydes (1) with phosphorane in diethylaniline under reflux gave only coumarins (3) in high yields except for 3-methoxysalicylaldehyde (1b).It was clarified that methoxy group(s) at C4 and C6 on 1 facilitated the formation of 3.
13C NMR SPECTRA AND STRUCTURE OF BUNGEIDIOL AND ITS TRASFORMATION PRODUCTS
Abyshev, A. Z.,Zmeikov, V. P.
, p. 270 - 276 (1982)
The results are given of a study of the 13C NMR spectra of the new terpenoid coumarin bungeidiol (I) and of the products of its transformation (II) and (III) and some model compounds (IV-VII).On the basis of the results obtained from these 13C NMR spectra and with the use of additive contributions depending on the nature and positions of various substituents (hydroxy and methoxy groups) in the aromatic ring, the structure (I) has been confirmed and a complete assignmant of the signals of all the carbon atoms both in the coumarin ring and in the aliphatic part of the molecule of (I) has been made.
Gold(I)-Catalyzed Intramolecular Hydroarylation of Phenol-Derived Propiolates and Certain Related Ethers as a Route to Selectively Functionalized Coumarins and 2 H-Chromenes
Cervi, Aymeric,Vo, Yen,Chai, Christina L. L.,Banwell, Martin G.,Lan, Ping,Willis, Anthony C.
, p. 178 - 198 (2020/12/22)
Methods are reported for the efficient assembly of a series of phenol-derived propiolates, including the parent system 56, and their Au(I)-catalyzed cyclization (intramolecular hydroarylation) to give the corresponding coumarins (e.g., 1). Simple syntheses of natural products such as ayapin (144) and scoparone (145) have been realized by such means, and the first of these subject to single-crystal X-ray analysis. A related process is described for the conversion of propargyl ethers such as 156 into the isomeric 2H-chromene precocene I (159), a naturally occurring inhibitor of juvenile hormone biosynthesis.
Anchimerically Assisted Selective Cleavage of Acid-Labile Aryl Alkyl Ethers by Aluminum Triiodide and N, N-Dimethylformamide Dimethyl Acetal
Sang, Dayong,Yue, Huaxin,Zhao, Zhengdong,Yang, Pengtao,Tian, Juan
, p. 6429 - 6440 (2020/07/14)
Aluminum triiodide is harnessed by N,N-dimethylformamide dimethyl acetal (DMF-DMA) for the selective cleavage of ethers via neighboring group participation. Various acid-labile functional groups, including carboxylate, allyl, tert-butyldimethylsilyl (TBS), and tert-butoxycarbonyl (Boc), suffer the conditions intact. The method offers an efficient approach to cleaving catechol monoalkyl ethers and to uncovering phenols from acetal-type protecting groups such as methoxymethyl (MOM), methoxyethoxymethyl (MEM), and tetrahydropyranyl (THP) chemoselectively.
Study of the Oxidative Cleavage Proposed in the Biogenesis of Transtaganolides/Basiliolides: Pyran-2-one Aromaticity-Mediated Regioselective Control and Biogenetic Implications
álvarez, José María,Jorge, Zacarías D.,Massanet, Guillermo M.
, (2020/03/05)
The synthetic feasibility of the oxidative cleavage: epoxidation of 7-O-geranylscopoletin followed by electrocyclic ring-opening, proposed in the biogenesis of transtaganolides/basiliolides is studied. Unlike the proposed pericyclic reactions, this pathway has not yet been addressed. Three synthetic strategies have been tested consisting of: i) Baeyer–Villiger oxidation of p-quinoids, ii) hydrolysis of quinone monoketals, or iii) direct fragmentation by using oxygen donors. Oxidation of the benzene ring of hydroxylated coumarins has been achieved using peroxyacids, but cleavage took place between undesired positions. The aromaticity conservation of the pyran-2-one cycle during oxidation is the controlling factor of these observed regioselectivities. The use of a 4,5-dihydroxy-2-methoxycinnamate model, in which the pyran-2-one ring does not exert influence on oxidation, has allowed the design of a synthetic sequence toward an analogue of the natural pyran-2-one isolated from Thapsia transtagana, key in the biogenesis. Mechanistic proposals for the obtained results as well as their biogenetic implications are raised.
