Flavonoid dimers as bivalent modulators for P-glycoprotein-based multidrug resistance: Structure-activity relationships

We recently described the modulatory activities of apigenin homodimers linked by ethylene glycol units in multidrug-resistant breast cancer and leukemic cells overexpressing ABCB1 (P-glycoprotein, P-gp). To further improve the potency of these dimers, a small library of flavonoid homodimers and hetero-dimers were synthesized, and their in vitro activity in reversing cellular resistance to paclitaxel, along with structure activity relationships (SAR), were evaluated using a P-gp-expressing human breast cancer cell line. Among these synthesized homodimers, many showed more potent reversing activity than that of the parent compound and verapamil. Two compounds in particular showed promising reversing activity at sub-micro-molar concentrations with no cytotoxic effects. Regarding SAR trends, flavonoid dimers with nonpolar and hydrophobic sub-stituents (e.g., methyl and ethyl groups) generally showed more potent resistance-reversing activity than that of dimers with polar and hydrophilic substituents (e.g. hydroxy groups) at the C3, C6, and C7 positions, but not at C5. In terms of sub-stituent steric bulk at C6, it was found that the flavonoid dimer with methyl groups was optimal, with bulkier substituents leading to lower reversing activity. Comparisons of flavonoid heterodimers with the corresponding homodimers revealed that the two binding sites on P-gp for flavonoid moieties are quite similar to each other. Besides paclitaxel, these new compounds also increased drug accumulation and enhanced the cytotoxicity of other cancer drugs such as doxorubicin, vincris-tine, and vinblastine by decreasing the IC 50 values 4 45-fold. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.link_to_subscribed_fulltex

Distinct cytokine and chemokine profiles in autism spectrum disorders

2016-2017 > Academic research: refereed > Publication in refereed journal201804_a bcmaVersion of RecordPublishe

Genetic diversity of Aspergillus species isolated from onychomycosis and Aspergillus hongkongensis sp. nov., with implications to antifungal susceptibility testing

Thirteen Aspergillus isolates recovered from nails of 13 patients (fingernails, n = 2; toenails, n = 11) with onychomycosis were characterized. Twelve strains were identified by multilocus sequencing as Aspergillus spp. (Aspergillus sydowii [n = 4], Aspergillus welwitschiae [n = 3], Aspergillus terreus [n = 2], Aspergillus flavus [n = 1], Aspergillus tubingensis [n = 1], and Aspergillus unguis [n = 1]). Isolates of A. terreus, A. flavus, and A. unguis were also identifiable by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The 13th isolate (HKU49T) possessed unique morphological characteristics different from other Aspergillus spp. Molecular characterization also unambiguously showed that HKU49T was distinct from other Aspergillus spp. We propose the novel species Aspergillus hongkongensis to describe this previously unknown fungus. Antifungal susceptibility testing showed most Aspergillus isolates had low MICs against itraconazole and voriconazole, but all Aspergillus isolates had high MICs against fluconazole. A diverse spectrum of Aspergillus species is associated with onychomycosis. Itraconazole and voriconazole are probably better drug options for Aspergillus onychomycosis