Recent advances in construction of small molecule-based fluorophore-drug conjugates

As a powerful tool to advance drug discovery, molecular imaging may provide new insights into the process of drug effect and therapy at cellular and molecular levels. When compared with other detection methods, fluorescence-based strategies are highly attractive and can be used to illuminate pathways of drugs’ transport, with multi-color capacity, high specificity and good sensitivity. The conjugates of fluorescent molecules and therapeutic agents create exciting avenues for real-time monitoring of drug delivery and distribution, both in vitro and in vivo. In this short review, we discuss recent developments of small molecule-based fluorophore-drug conjugates, including non-cleavable and cleavable ones, that are capable of visualizing drug delivery.     

Enhancement of Transport of D-Melphalan Analogue by Conjugation with L-Glutamate across Bovine Brain Microvessel Endothelial Cell Monolayers

Abstract

In this paper, the L-glutamate (L-Glu) transport system was targeted to improve the delivery of a model compound, p-di(hydroxyethyl)-amino-D-phenylalanine (D-MOD), through the blood-brain barrier (BBB) in vitro cell culture model. D-MOD is an analogue of an antitumor agent D-melphalan. To target the L-Glu transport system, D-MOD was conjugated to L-Glu to give D-MOD-L-Glu conjugate. D-MOD and D-MOD-L-Glu transport properties were evaluated using the bovine brain microvessel endothelial cell (BBMEC) monolayers. The results suggest that D-MOD-L-Glu conjugate permeates through the BBMEC monolayers more readily than the parent D-MOD. The improvement of transport may be due to the recognition of D-MOD-L-Glu by the L-Glu transport system. The transport mechanism was evaluated using several different experiments including: (a) concentration-dependent studies; (b) temperature-dependent studies; (c) substrate inhibition studies; and (d) metabolic inhibitor studies. The D-MOD-L-Glu transport was inhibited by the change of temperature from 37°C to 4°C. At higher concentrations, the transport of D-MOD-L-Glu reached plateau due to saturation. Furthermore, some amino acids (i.e., L-Glu, L-Asp, D-Asp, and L-Gln) inhibited the transport of D-MOD-L-Glu; presumably the conjugate was competing with these amino acids for the same transport system. Metabolic inhibitors (i.e., 2,4-dinitrophenol and sodium azide) suppressed the transport of the conjugate. However, the conjugate was not transported by monocarboxylic acid, dipeptide and neutral amino acid transporters. In conclusion, the L-Glu transport system can be utilized to facilitate a non-permeable drug across the BBB by conjugating the drug with L-Glu amino acid.     

基于水解酶的抗寄生虫前药研究

前药策略已被广泛应用于各种基于药剂学、药代动力学和药效学的药物优化。多数涉及前药转化的酶都属于水解酶,其中以酯水解酶和酰胺水解酶的研究最为广泛。本文综述了基于这两种水解酶的抗寄生虫前药的研究进展。     

福司氟康唑合成新工艺

目的 优化福司氟康唑合成工艺。方法 以廉价易得氟康唑为起始原料,使用三氯氧磷进行氯磷酸酯化,之后与苄 醇进行缩合,得到中间体 c,将中间体 c 用 Pd/C 催化,以甲酸铵为氢供体,进行脱苄基,经过酸化,析晶,得福司氟康唑。结 果 总收率达 70.7%,纯度为 98.8%,产品结构经 1 H NMR 确证。结论 本文设计了一条新的合成路线,该合成过程操作简单, 起始原料便宜易得,反应条件温和,收率高,易于工业化。     

Kidney–targeted drug delivery systems

Kidney-targeted drug delivery systems represent a promising technology to improve drug efficacy and safety in the treatment of renal diseases. In this review, we summarize the strategies that have been employed to develop kidney-targeted drug delivery systems. We also describe how macromolecular carriers and prodrugs play crucial roles in targeting drugs to particular target cells in the kidney. New technologies render it possible to create renal targeting conjugates and other delivery systems including nanoparticles and liposomes present promising strategies to achieve the goal of targeting drugs to the kidney.KEY WORDS: Kidney-targeted, Prodrug, Macromolecular carrier, Nanoparticles, Liposomes     

Full-profile pharmacokinetics,anticancer activity and toxicity of an extended release trivalent PEGylated irinotecan prodrug

Irinotecan is an anticancer topoisomerase I inhibitor that acts as a prodrug of the active metabolite,SN-3 8.Unfortunately,the limited utility of irinotecan is attributed to its pH-dependent stability,short half-life and dose-limiting toxicity.To address this problem,a novel trivalent PEGylated prodrug(PEG-[Irinotecan]₃) has been synthesized and its full-profile pharmacokinetics,antitumor activity and toxicity compared with those of irinotecan.The results show that after intravenous a...     

Advances in Nucleotide Antiviral Development from Scientific Discovery to Clinical Applications: Tenofovir Disoproxil Fumarate for Hepatitis B

Exploration of naturally occurring chemical structures for medicinal uses has received significant interest in drug discovery and development research in the past few decades. None have had more success or products of greater clinical efficacy than synthetic analogs of nucleosides and nucleotides, especially as antiviral drugs. Nucleos(t)ide antivirals are synthetic analogs of the natural building blocks of DNA or RNA. This review focuses on the developmental path of tenofovir disoproxil fumarate (TDF), a prodrug of a nucleotide analog and its clinical applications as a first-line antiviral for chronic hepatitis B (CHB).Tenofovir is a potent antiviral compound, but has poor oral availability. The disoproxil fumarate (DF) prodrug moiety greatly enhances intestinal absorption allowing it to become an oral medication. Tenofovir is activated intracellularly, and the incorporation into HBV DNA prevents further elongation thus terminating replication. In patients with CHB, TDF has demonstrated broad, potent and sustained virologic response. Maintenance of viral suppression for up to 5 years resulted in regression of fibrosis and cirrhosis. No tenofovir-resistant HBV variants have been detected in patients after long-term use. The efficacy and safety profiles reported from cohort studies of clinical practices were consistent with those observed in registration trials.Continuous development includes a new oral prodrug, tenofovir alafenamide fumarate (TAF), which has enhanced delivery of tenofovir to target cells compared to TDF.     

A Novel Class of Antitumor Prodrug, 1-(2'-Oxopropyl)-5-fluorouracil (OFU001), That Releases 5-Fluorouracil upon Hypoxic Irradiation

We have been developing prodrugs of anticancer agents such as 5‐fluorouracil (5‐FU) that are activated by irradiation under hypoxic conditions via one‐electron reduction. Among them, OFU001 [1‐(2′‐oxopropyl)‐5‐fluorouracil] is a prototype radiation‐activated prodrug. In this study, we investigated the radiation chemical reactivity and the biological effects of OFU001. This prodrug is presumed to release 5‐FU through incorporation of hydrated electrons into the antibonding σ* orbital of the C(1′)‐N(1) bond. Hydrated electrons are active species derived from radiolysis of water, but are readily deactivated by O₂ into superoxide anion radicals () under conditions of aerobic irradiation. Therefore, 5‐FU release occurs highly specifically upon irradiation under hypoxic conditions. OFU001 dissolved in phosphate buffer released 5‐FU with a G‐value (mol number of molecules that are decomposed or produced by 1 J of absorbed radiation energy) of 1.9×10^?7 mol/ J following hypoxic irradiation, while the G‐value for 5‐FU release was 1.0×10^?8 mol/J following aerobic irradiation. However, the G‐values for decomposition of OFU001 were almost the same, i.e., 3.4×10^?7 mol/J following hypoxic irradiation and 2.5×10^?7 mol/J following aerobic irradiation. When hypoxically irradiated (7.5–30 Gy) OFU001 was added to murine SCCVII cells for 1–24 h, a significant cell‐killing effect was observed. The degree of this cytotoxicity was consistent with that of authentic 5‐FU at the corresponding concentrations. On the other hand, cytotoxicity was minimal when the cells were treated with aerobically irradiated or unirradiated OFU001. This compound had no radiosensitizing effect against SCCVII cells under either aerobic or hypoxic conditions when the drug was removed immediately after irradiation. Since hypoxia is generally most marked in tumors and irradiation is applied at the tumor site, this concept of prodrug design appears to be potentially useful for selective tumor treatment with minimal adverse effects of anticancer agents.     

Prodrug research: futile or fertile?

The objective of this Commentary is to help clarify and illustrate what prodrugs are, what they are not, which benefits they can offer, and what their limits are. To this end, a number of criteria of classification and evaluation are presented. This is followed by a discussion of the pharmaceutical, pharmacokinetic and pharmacodynamic objectives of prodrug research. Recent examples (e.g. oseltamivir, bambuterol, capecitabine, clopidogrel and tirapazamine) are discussed in a biochemical perspective to illustrate these objectives and to demonstrate some of the therapeutic benefits afforded by successful prodrugs. Attention is also called to the fact that the in vitro and in vivo behavior of prodrug candidates may differ from that of the parent drug in ways that go beyond the original pharmaceutical, pharmacokinetic or pharmacodynamic objective being pursued. We conclude that prodrugs offer a viable strategy to disentangle pharmacodynamic and pharmacokinetic optimization.     

Improving the ocular absorption of phenylephrine

An oxazolidine prodrug of phenylephrine and the base form of phenylephrine were synthesized, suspended in sesame oil, and tested for mydriatic activity against phenylephrine HCl. The HCl salt was formulated as a viscous aqueous solution and as a sesame oil suspension. A dosing volume of 10 microliter was instilled into rabbit eyes and the pupillary diameter was measured over time. A 0.045 M prodrug suspension was judged equal in mydriatic activity to a 0.45 M viscous solution of phenylephrine HCl with the exception that the time of maximum response occurred 60 min earlier with the prodrug. When phenylephrine base was suspended in sesame oil at 0.045, 0.12, and 0.45 M, the mydriatic activity was also greater than equimolar suspensions of phenylephrine HCl. The pH of tear fluids was also measured over time and found to rise 1.1, 0.70, and 0.30 pH units for 0.45, 0.12, and 0.045 M suspensions of the base form but remain unchanged when phenylephrine HCl was instilled in the rabbit eye. The greater activity associated with the base form of phenylephrine was judged a result of the change in pH to favour the absorption of phenylephrine. This latter approach should be applicable to either weak acids or weak bases with pKa values outside of the normal pH range (7-8) of the tears and in concentrations greater than 0.045 M suspended in a non-aqueous vehicle.