2009-24-7Relevant academic research and scientific papers
Synthesis and properties of peptide nucleic acids containing a psoralen unit.
Okamoto,Tanabe,Saito
, p. 925 - 927 (2001)
We prepared the psoralen PNA unit from 8-methoxypsoralen and synthesized various PNAs containing psoralen by a typical (t)()Boc method. PNAs containing psoralen (P-PNA) at strand end formed a stable duplex with complementary DNA. The hybridization of P-PNA with complementary DNA resulted in a considerable decrease of the psoralen fluorescence.
Synthesis of 8-geranyloxypsoralen analogues and their evaluation as inhibitors of CYP3A4
Row,Brown,Stachulski,Lennard
, p. 3865 - 3871 (2006)
Furanocoumarins have been shown to inhibit CYP3A4 in vitro with varying degrees of potency [Pharmacogenetics 1997, 7, 391-396; Chem. Res. Toxicol. 1998, 11, 252-259; Drug Metab. Dispos. 1997, 25, 1228-1233; Br. J. Pharmacol. 2000, 130, 1369-1377]. In this study, we report the effects of a series of novel furanocoumarins based on the naturally occurring derivative 8-geranylepoxypsoralen which has been shown to be a more potent inhibitor of CYP3A4 than its 5-position-substituted counterpart bergamottin [Drug Metab. Dispos. 2000, 28, 766-771; Jpn. J. Pharmacol. 2000, 82, 122-129]. Compounds were designed, synthesised and tested for their ability to inhibit CYP3A4 activity in human liver microsomes using testosterone as the marker substrate. Both the saturated and unsaturated phenolic furanocoumarin derivatives were found to be inactive. However, the 8-alkyloxy-furanocoumarin analogues were shown to inhibit CYP3A4 activity in a dose dependent manner, with IC50 values ranging from 0.78 ± 0.11 to 3.93 ± 0.53 μM. The reduced furan derivative dihydro-8-geranyloxypsoralen showed a 4-fold decrease in inhibitory potency, suggesting that the furan moiety plays a role in the interaction between these compounds and CYP3A4.
Efficient cleavage of DNA by iron(III) triazacyclononane derivatives
Silver, Gail C.,Trogler, William C.
, p. 3983 - 3993 (1995)
Compounds based on (1,4,7-trimethyl-1,4,7-triazacyclononane)iron(III) chloride have been synthesized. Exceedingly low concentrations (approximately 0.5 μM) of these reagents are required to effect single-stranded oxidative cleavage of plasmid DNA at physiological pH and temperature. Approximately 3 breaks per plasmid per micromolar of reagent occur in 1 h at 37°C. The addition of dithiothreitol dramatically increased the effectiveness of these compounds; only 0.05 μM of reagent was required for DNA cleavage. When psoralen (a DNA photocross-linking agent) was attached to the iron complex, irradiation further increased the cleavage efficiency. The DNA cleaving abilities rival those of the cytotoxic antitumor drug bleomycin. Unlike bleomycin, the synthetic agents cut DNA with little sequence specificity. The lability of the chloride ligands, the hard acid character of iron(III), and the absence of base specificity in the DNA cleaving reaction suggest that a cationic iron species binds to the phosphate backbone of DNA. The reaction's dependence on reductants and dissolved oxygen suggests that it proceeds by a redox mechanism. Crystals of (1,4,7-trimethyl-1,4,7-triazacyclononane)FeCl3 (L'FeCl3) belong to the monoclinic space group P21/c, with a = 12.321(2) A?, b = 7.3220(10) A?, c = 15.903(3) A?, V = 1434.7(5) A?3, and Z = 4 at 293 K. Refinement of 145 least squares parameters for 2613 independent reflections with F > 4.0σ(F) converged to R = 3.43% and R(w) = 6.45%. The coordination geometry around iron(III) approximates a trigonally distorted octahedron. The N-Fe-N bond angles (77.8°-78.8°) are compressed, while the Cl-Fe-Cl angles (96.7°-97.0°) are expanded from the octahedral value.
Noncovalent attachment of psoralen derivatives with DNA: Hartree-Fock and density functional studies on the probes.
El-Gogary, Tarek M,El-Gendy, Eman M
, p. 2635 - 2644 (2003)
Two psoralen derivatives (probes) were prepared. Their geometries were optimized at the Hartree-Fock (HF) and Density Functional (B3LYP) levels employing 6-31G** and cc-pVDZ basis sets. Their interaction with DNA was investigated using spectrophotometric and computational techniques. Both of them have shown strong binding to calf thymus DNA. The red-shift and hypochromism that detected in the spectrum were taken as an evidence for the strong interaction between these probes and DNA. The spectrophotometric DNA titration data were treated by two different methodologies to calculate the intercalation affinity. Half-reciprocal plots gave binding constants of 5.5065 x 10(4) and 6.4727 x 10(4) for 8-butoxypsoralen (8-BOP) and 8-hexoxypsoralen (8-HOP), respectively. Schatchard plots gave a comparable intercalation binding constants and also the surface binding constants along with the number of intercalated probe molecules per base pair. The interaction between these probes and DNA were studied theoretically. The energy of interaction was computed using molecular mechanics method. Strength of interaction of these probes with different types of DNA was computed and compared. Calculated energies of interaction were compared with the observed intercalation affinities. HOMO and LUMO energies were computed and used to account for the strength of interaction.
A clickable psoralen to directly quantify DNA interstrand crosslinking and repair
Evison, Benjamin J.,Actis, Marcelo L.,Fujii, Naoaki
, p. 1071 - 1078 (2016)
DNA interstrand crosslinks (ICLs) represent physical obstacles to advancing replication forks and transcription complexes. A range of ICL-inducing agents have successfully been incorporated into cancer therapeutics. While studies have adopted UVA-activated psoralens as model ICL-inducing agents for investigating ICL repair, direct detection of the lesion has often been tempered by tagging the psoralen scaffold with a relatively large reporter group that may perturb the biological activity of the parent psoralen. Here a minimally-modified psoralen probe was prepared featuring a small alkyne handle suitable for click chemistry. The psoralen probe, designated 8-propargyloxypsoralen (8-POP), can be activated by UVA in vitro to generate ICLs that are susceptible to post-labeling with an azide-tagged fluorescent reporter via a copper-catalyzed reaction. A modified alkaline comet assay demonstrated that UVA-activated 8-POP proficiently generated ICLs in cells. Cellular 8-POP-DNA lesions were amenable to click-mediated ligation to fluorescent reporters in situ, which permitted their detection and quantitation by fluorescence microscopy and flow cytometry. Small molecule DNA repair inhibitors to 8-POP-treated cells attenuated the removal of 8-POP-DNA lesions, validating 8-POP as an appropriate probe for investigating cellular ICL repair. The post-labeling strategy applied in this study is inexpensive, rapid and highly modular in nature with the potential for multiple applications in DNA repair studies.
MONOTERPENOID FURANOCOUMARIN LACTONES FROM CLAUSENA ANISATA
Lakshmi, Vijai,Prakash, Dhan,Raj, Kanwal,Kapil, Randhir S.,Popli, Satya P.
, p. 2629 - 2632 (1984)
A reinvestigation of Clausena anisata has yielded imperatorin, xanthotoxol, lansamide-I and three new furanocoumarin lactone derivatives: indicolactone, anisolactone and 2',3'-epoxyanisolactone.The structures of these compounds have been elucidated by a combination of spectroscopic and chemical methods.Key Word Index - Clausena anisata; Rutaceae; furanocoumarin lactone derivatives; indicolactone; anisolactone; 2',3'-epoxyanisolactone.
Synthesis and In Vitro Biological Evaluation of Psoralen-Linked Fullerenes
Hashimoto, Akiko,Takamura-Enya, Takeji,Oda, Yoshimitsu
, p. 1403 - 1411 (2019)
Photodynamic therapy (PDT) is a widely used medicinal treatment for the cancer therapy that utilizes the combination of a photosensitizer (PS) and light irradiation. In this study, we synthesized two novel C60 fullerene derivatives, compounds 1 and 2, with a psoralen moiety that can covalently bind to DNA molecules via cross-linking to pyrimidine under photoirradiation. Along with several fullerene derivatives, the biological properties of several novel compounds have been evaluated. Compounds 1 and 2, which have been shown to induce the production of hydroxyl radicals using several ROS detecting reagents, induced DNA strand breaks with relatively weak activities in the in vitro detection system using a supercoiled plasmid. However, the psoralen-bound fullerene with carboxyl groups (2) only showed genotoxicity in the genotoxicity assay system of the umu test. Compound 2 was also seen to have cytotoxic activities in several cancer cell lines at higher doses compared to water-soluble fullerenes.
WAMPETIN, A FUROCOUMARIN FROM CLAUSENA WAMPI
Khan, Nizam U.,Naqvi, S. W. I.,Ishratullah, Khwaja
, p. 2624 - 2625 (1983)
A new furocoumarin wampetin has been isolated from Clausena wampi (syn.Clausena lansium).The structure was established from 1H NMR, 13C NMR, MS and chemical data. - Key Word Index: Clausena wampi (Syn.Clausena lansium); Rutaceae; wampetin; furocoumarin; 13C NMR data.
Biotransformation of isoimperatorin and imperatorin by Glomerella cingulata and β-secretase inhibitory activity
Marumoto, Shinsuke,Miyazawa, Mitsuo
, p. 455 - 459 (2010)
Biotransformation studies conducted on the furanocoumarins isoimperatorin (1) and imperatorin (3) have revealed that 1 was metabolized by Glomerella cingulata to give the corresponding reduced acid, 6,7-furano-5-prenyloxy hydrocoumaric acid (2), and 3 was transformed by G. cingulata to give the dealkylated metabolite, xanthotoxol (4) in high yields (83% and 81%), respectively. The structures of the new compound 2 have been established on the basis of spectral data. The metabolites 2 and 4 were tested for the β-secretase (BACE1) inhibitory activity in vitro, and metabolite 2 slightly inhibited the β-secretase activity with an IC50 value of 185.6 ± 6.8 μM. The metabolite 4 was less potent activity than compounds 1-3. In addition, methyl ester (2Me), methyl ether (2a) and methyl ester and ether (2aMe) of 2 were synthesized, and investigated for the ability to inhibit β-secretase. Compound 2aMe exhibited the best β-secretase inhibitory activity at the IC50 value 16.2 ± 1.2 μM and found to be the 2aMe showed competitive mode of inhibition against β-secretase with Ki value 11.3 ± 2.8 μM.
Design, synthesis, and evaluation of new series of Imperatorin analogs with potential vasodilatory activity
Hou, Ya-Jing,Wang, Cheng,Wang, Tao,Huang, Li-Min,Lin, Yuan-Yuan,He, Huai-Zhen
, p. 43 - 50 (2019)
Two series of imperatorin analogs were synthesized based on our previous research and evaluated for their vasodilatation activities on in vitro rat mesenteric artery, basilar artery, and renal artery ring models. Target compounds were characterized by infrared, 1H NMR, and mass spectra. Most derivatives possessed significant vasodilatory activity on the mesenteric artery, and compound 3a exhibited favorable and broad vasodilatation activities on three kinds of rat artery ring models. The pharmacological results indicated that introducing nitrogen-contained ring in side chain or large steric hindrance at the distal end could increase the vasodilatory activity. Further, replacement of oxygen atom (–O–) in the skeleton of furocoumarin derivatives with nitrogen (–NH–) could cause the decrease of vasodilatory activity. The molecular docking also indicated that compound 3a showed a best affinity with α-1C receptor (PDB ID: 3G43). All these results suggested compound 3a would be a potential vasodilatory agent for hypertension.
