Estimating the Lipophilicity of Natural Products Using a Polymeric Reversed Phase HPLC Method

Zheng, Bo; West, Lyndon M.

doi:10.1080/10826070903430464

Cited by 13 publications

(10 citation statements)

References 21 publications

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“…Removing the methyl group on HSL420 reduced the c log P even further to 3.23 (HSN748) . The ranking of log P values can be derived from retention times of compounds on C18 columns . In concordance with the calculated log P values, the high-performance liquid chromatography (HPLC) retention times of the analogs showed corresponding trends (Table ).…”

Section: Resultsmentioning

confidence: 77%

Nicotinamide–Ponatinib Analogues as Potent Anti-CML and Anti-AML Compounds

et al. 2020

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Ponatinib is a multikinase inhibitor that is used to treat chronic myeloid leukemia patients harboring mutated ABL1(T315I) kinase. Due to the potent inhibition of FLT3, RET, and fibroblast growth factor receptors (FGFRs), it is also being evaluated against acute myeloid leukemia (AML), biliary, and lung cancers. The multikinase inhibition profile of ponatinib may also account for its toxicity, thus analogs with improved kinase selectivity or different kinase inhibition profiles could be better tolerated. The introduction of nitrogen into drug compounds can enhance efficacy and drug properties (a concept called “necessary nitrogen”). Here, we introduce additional nitrogen into the benzamide moiety of ponatinib to arrive at nicotinamide analogs. A nicotinamide analogue of ponatinib, HSN748, retains activity against FLT3, ABL1, RET, and PDGFRα/β but loses activity against c-Src and P38α. MNK1 and 2 are key kinases that phosphorylate eIF4E to regulate the protein translation complex. MNK also modulates mTORC1 signaling and contributes to rapamycin resistance. Inhibitors of MNK1 and 2 are being evaluated for anticancer therapy. Ponatinib is not a potent inhibitor of MNK1 or 2, but the nicotinamide analogs are potent inhibitors of MNKs. This illustrates a powerful demonstration of the necessary nitrogen concept to alter both the potency and selectivity of drugs.

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Section: Resultsmentioning

confidence: 77%

Nicotinamide–Ponatinib Analogues as Potent Anti-CML and Anti-AML Compounds

et al. 2020

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“…RP-HPLC is a useful method for preliminary research into drug lipophilicity due to the small amount of compound required [ 40 ]. The method is based on the evaluation of the retention factor (k).…”

Section: Resultsmentioning

confidence: 99%

Microbial Synthesis and Evaluation of Fungistatic Activity of 3-Butyl-3-hydroxyphthalide, the Mammalian Metabolite of 3-n-Butylidenephthalide

Gach

Olejniczak

Krężel

et al. 2021

IJMS

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Phthalides are bioactive compounds that naturally occur in the family Apiaceae. Considering their potentially versatile applications, it is desirable to determine their physical properties, activity and metabolic pathways. This study aimed to examine the utility of whole-cell biocatalysts for obtaining 3-butyl-3-hydroxyphthalide, which is the metabolite formulated during mammalian metabolism of 3-n-butylidenephthalide. We performed transformations using 10 strains of fungi, five of which efficiently produced 3-butyl-3-hydroxyphthalide. The product yield, determined by high-performance liquid chromatography, reached 97.6% when Aspergillus candidus AM 386 was used as the biocatalyst. Increasing the scale of the process resulted in isolation yields of 29–45% after purification via reversed-phase thin layer chromatography, depending on the strain of the microorganism used. We proposed different mechanisms for product formation; however, hydration of 3-n-butylidenephthalide seems to be the most probable. Additionally, all phthalides were tested against clinical strains of Candida albicans using the microdilution method. Two phthalides showed a minimum inhibitory concentration, required to inhibit the growth of 50% of organisms, below 50 µg/mL. The 3-n-butylidenephthalide metabolite was generally inactive, and this feature in combination with its low lipophilicity suggests its involvement in the detoxification pathway. The log P value of tested compounds was in the range of 2.09–3.38.

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“…We analyzed reversed-phase high-performance liquid chromatography (HPLC) -derived gradient retention time (t R ) values of TPP-(CH 2 ) n -COOH, n = 2-7 (L2-L7) under a wateracetonitrile gradient to understand the chromatographic hydrophobicity of these targeting ligands (34,35). As shown in SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

Nanotechnology-mediated crossing of two impermeable membranes to modulate the stars of the neurovascular unit for neuroprotection

Surnar

Basu

Banik

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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The success of nanoparticle-mediated delivery of antioxidant and antiinflammatory-based neuroprotectants to the brain to improve neuronal functions in neurodegenerative diseases has demonstrated lesser impact instead of achieving its full potential. We hypothesized that these failures were due to a combination of parameters, such as: (i) unavailability of a delivery vehicle, which can reproducibly and efficiently transport through the brain capillary endothelium; (ii) inefficient uptake of therapeutic nanoparticles in the neuronal cell population; and (iii) limited ability of a single nanoparticle to cross the two most-impermeable biological barriers, the blood–brain barrier and mitochondrial double membrane, so that a nanoparticle can travel through the brain endothelial barrier to the mitochondria of target cells where oxidative damage is localized. Herein, we demonstrate optimization of a biodegradable nanoparticle for efficient brain accumulation and protection of astrocytes from oxidative damage and mitochondrial dysfunctions to enhance the neuroprotection ability of astrocytes toward neurons using neurodegeneration characteristics in SOD1G93A rats. This biodegradable nanomedicine platform with the ability to accumulate in the brain has the potential to bring beneficial effects in neurodegenerative diseases by modulating the stars, astrocytes in the brain, to enhance their neuroprotective actions.

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Estimating the Lipophilicity of Natural Products Using a Polymeric Reversed Phase HPLC Method

Cited by 13 publications

References 21 publications

Nicotinamide–Ponatinib Analogues as Potent Anti-CML and Anti-AML Compounds

Nicotinamide–Ponatinib Analogues as Potent Anti-CML and Anti-AML Compounds

Microbial Synthesis and Evaluation of Fungistatic Activity of 3-Butyl-3-hydroxyphthalide, the Mammalian Metabolite of 3-n-Butylidenephthalide

Nanotechnology-mediated crossing of two impermeable membranes to modulate the stars of the neurovascular unit for neuroprotection

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