Development Of Prodrugs Research Articles

Calixarene: A Versatile Material for Drug Design and Applications

The therapy of various diseases by the drugs entrapped in calixarene derivatives is gaining attraction of researchers nowadays. Calixarenes are macrocyclic nano-baskets which belong to cavitands class of host-guest chemistry. They are the marvelous hosts with distinct hydrophobic three dimensional cavities to entrap and encapsulate biologically active guest drugs. Calixarene and its derivatives develop inclusion complexes with various types of drugs and vitamins for their sustained/targeted release. Calixarene and its derivatives are used as carriers for anti-cancer, anti-convulsant, anti-hypertensive, anthelmentic, anti-inflammatory, antimicrobial and antipsychotic drugs. They are the important biocompatible receptors to improve solubility, chemical reactivity and decrease cytotoxicity of poorly soluble drugs in supramolecular chemistry. This review focuses on the calixarene and its derivatives as the state-of-the-art in host-guest interactions for important drugs. We have also critically evaluated calixarenes for the development of prodrugs.

Molecular Pathways: Hypoxia-Activated Prodrugs in Cancer Therapy.

Hypoxia is a known feature of aggressive solid tumors as well as a critical hallmark of the niche in aggressive hematologic malignances. Hypoxia is associated with insufficient response to standard therapy, resulting in disease progression and curtailed patients' survival through maintenance of noncycling cancer stem-like cells. A better understanding of the mechanisms and signaling pathways induced by hypoxia is essential to overcoming these effects. Recent findings demonstrate that bone marrow in the setting of hematologic malignancies is highly hypoxic, and that progression of the disease is associated with expansion of hypoxic niches and stabilization of the oncogenic hypoxia-inducible factor-1alpha (HIF1α). Solid tumors have also been shown to harbor hypoxic areas, maintaining survival of cancer cells via the HIF1α pathway. Developing new strategies for targeting hypoxia has become a crucial approach in modern cancer therapy. The number of preclinical and clinical trials targeting low-oxygen tumor compartments or the hypoxic bone marrow niche via hypoxia-activated prodrugs is increasing. This review discusses the development of the hypoxia-activated prodrugs and their applicability in treating both hematologic malignancies and solid tumors. Clin Cancer Res; 23(10); 2382-90. ©2017 AACR.

Novel lipid-mimetic prodrugs delivering active compounds to adipose tissue

Obesity and associated pathologies are a dramatically growing problem. New therapies to prevent and/or cure them are strongly needed. Adipose tissue is a logical target for pharmacological intervention, since it is now recognized to exert an important endocrine function, secreting a variety of adipokines affecting, for example, adiposity and insulin resistance. This proof of principle work focuses on the development of novel lipid-mimetic prodrugs reaching fat deposits by the same lymphatic absorption route followed by dietary triglycerides.Pterostilbene, a natural phenolic compound with potential anti-obesity effects, was used as model “cargo”, attached via a carbamate group to an ω-aminodecanoate chain linked to either position 1 or position 2 of the glycerol moiety of synthetic triglycerides. The prodrugs underwent position-selective hydrolysis when challenged with pancreatic lipases in vitro. Pterostilbene-containing triglycerides as well as pterostilbene and its metabolites were present in the adipose tissue of mice fed an obesogenic diet containing one or the other of the derivatives.For the first time this approach is used to deliver an obesity antagonist to the adipose tissue. The results demonstrate the feasibility of delivering active compounds to adipose tissue by reversibly incorporating them into triglyceride-mimetic structures. Upon release in the target site these compounds are expected to exert their pharmacological activity precisely where needed.

Isolation and characterization of anticancer flavone chrysin (5,7-dihydroxy flavone)-producing endophytic fungi from Passiflora incarnata L. leaves

Chrysin (5,7-dihydroxy flavone, ChR) is a flavone of plant origin, possessing numerous biomedical properties, such as antimicrobial, anti-inflammatory, anti-diabetic, anxiolytic, hepatoprotective, anti-aging and anticonvulsant activities. In this study, chrysin-producing fungal endophytes (A. alternata KT380662, C. capsici KT373967, and C. taiwanense PI-3 KX580307) were isolated from the leaves of Passiflora incarnata L. and characterised via morphology and internal transcribed spacer (ITS) sequences. Thin layer chromatography and high-performance liquid chromatography profiles of fungal extracts showed Rf values and retention times that closely match those of standard chrysin (ChR). Further, the production of fungal chrysin (FChR) was confirmed through UV-vis spectroscopy, FT-IR, LC-ESI-MS, and 1H1 NMR analysis. Among the isolated strains, A. alternata KT380662 was identified as having a high-level of ChR production, with rates measuring approximately 846 mg L−1. On the other hand, in vitro anticancer and radical scavenging studies proved that FChR has significant cytotoxic activity against human liver carcinoma cells (HepG2). These results clearly imply that the isolated A. alternata KT380662 could serve as an alternative source for the commercial production of ChR, which holds anticancer and radical scavenging activities, and the fungal-derived ChR can be used in chemotherapy or in prodrug development.

Covalent Guanosine Mimetic Inhibitors of G12C KRAS.

Ras proteins are members of a large family of GTPase enzymes that are commonly mutated in cancer where they act as dominant oncogenes. We previously developed an irreversible guanosine-derived inhibitor, SML-8-73-1, of mutant G12C RAS that forms a covalent bond with cysteine 12. Here we report exploration of the structure-activity relationships (SAR) of hydrolytically stable analogues of SML-8-73-1 as covalent G12C KRAS inhibitors. We report the discovery of difluoromethylene bisphosphonate analogues such as compound 11, which, despite exhibiting reduced efficiency as covalent G12C KRAS inhibitors, remove the liability of the hydrolytic instability of the diphosphate moiety present in SML-8-73-1 and provide the foundation for development of prodrugs to facilitate cellular uptake. The SAR and crystallographic results reaffirm the exquisite molecular recognition that exists in the diphosphate region of RAS for guanosine nucleotides which must be considered in the design of nucleotide-competitive inhibitors.

Click and Release: A Chemical Strategy toward Developing Gasotransmitter Prodrugs by Using an Intramolecular Diels-Alder Reaction.

Prodrug strategies have been proven to be a very effective way of addressing delivery problems. Much of the chemistry in prodrug development relies on the ability to mask an appropriate functional group, which can be removed under appropriate conditions. However, developing organic prodrugs of gasotransmitters represent unique challenges. This is especially true with carbon monoxide, which does not have an easy "handle" for bioreversible derivatization. By taking advantage of an intramolecular Diels-Alder reaction, we have developed a prodrug strategy for preparations of organic CO prodrugs that are stable during synthesis and storage, and yet readily release CO with tunable release rates under near physiological conditions. The effectiveness of the CO prodrug system in delivering a sufficient quantity of CO for possible therapeutic applications has been studied using a cell culture anti-inflammatory assay and a colitis animal model. These studies fully demonstrate the proof of concept, and lay a strong foundation for further medicinal chemistry work in developing organic CO prodrugs.

Click and Release: A Chemical Strategy toward Developing Gasotransmitter Prodrugs by Using an Intramolecular Diels–Alder Reaction

AbstractProdrug strategies have been proven to be a very effective way of addressing delivery problems. Much of the chemistry in prodrug development relies on the ability to mask an appropriate functional group, which can be removed under appropriate conditions. However, developing organic prodrugs of gasotransmitters represent unique challenges. This is especially true with carbon monoxide, which does not have an easy “handle” for bioreversible derivatization. By taking advantage of an intramolecular Diels–Alder reaction, we have developed a prodrug strategy for preparations of organic CO prodrugs that are stable during synthesis and storage, and yet readily release CO with tunable release rates under near physiological conditions. The effectiveness of the CO prodrug system in delivering a sufficient quantity of CO for possible therapeutic applications has been studied using a cell culture anti‐inflammatory assay and a colitis animal model. These studies fully demonstrate the proof of concept, and lay a strong foundation for further medicinal chemistry work in developing organic CO prodrugs.

Native Design of Soluble, Aggregation-Resistant Bioactive Peptides: Chemical Evolution of Human Glucagon.

Peptide-based therapeutics commonly suffer from biophysical properties that compromise pharmacology and medicinal use. Structural optimization of the primary sequence is the usual route to address such challenges while trying to maintain as much native character and avoiding introduction of any foreign element that might evoke an immunological response. Glucagon serves a seminal physiological role in buffering against hypoglycemia, but its low aqueous solubility, chemical instability, and propensity to self-aggregate severely complicate its medicinal use. Selective amide bond replacement with metastable ester bonds is a preferred approach to the preparation of peptides with biophysical properties that otherwise inhibit synthesis. We have recruited such chemistry in the design and development of unique glucagon prodrugs that have physical properties suitable for medicinal use and yet rapidly convert to native hormone upon exposure to slightly alkaline pH. These prodrugs demonstrate in vitro and in vivo pharmacology when formulated in physiological buffers that are nearly identical to native hormone when solubilized in conventional dilute hydrochloric acid. This approach provides the best of both worlds, where the pro-drug delivers chemical properties supportive of aqueous formulation and the native biological properties.

Opioids and Cannabis: Myths and Misperceptions

Back to table of contents Previous article Next article Monitoring the MeetingFull AccessOpioids and Cannabis: Myths and MisperceptionsRasna Patel, M.D., Amit Mistry, M.D.Rasna PatelSearch for more papers by this author, M.D., Amit MistrySearch for more papers by this author, M.D.Published Online:16 Mar 2017https://doi.org/10.1176/appi.ajp-rj.2016.111107AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail What We KnowDr. Nora Volkow, Director of the National Institute on Drug Abuse, discussed the opioid epidemic, a public health issue that plagues America. The opioid epidemic was put into the limelight by the media when opioid overdose mortalities surpassed mortalities by motor vehicle accidents in the 1990s, a time in which opioid prescriptions increased drastically. This was fueled by the growing concern of inadequate assessment and treatment of the “fifth vital sign”: patients’ pain. The ubiquity of pain, easy access to narcotic medications, and lack of public awareness about their addictive potential led to widespread misuse. Since 1999, opioid prescriptions have quadrupled, and opioid overdose is on the rise, especially in women ages 45–55 years-old (1).What Is NewIn March 2016, the Centers for Disease Control and Prevention released new opioid prescribing guidelines related to chronic noncancer pain (2). Many states have now mandated the use of prescription monitoring programs before prescribing opioids and other controlled substances in efforts to reduce misuse and make physicians aware of patients’ prescription habits. The biggest impact has come from building awareness of the issue. At the National Prescription Drug Abuse and Heroin Summit in March 2016, President Barack Obama spoke regarding the opioid epidemic. He at once acknowledged the gravity of the problem and rallied America to come together to address the epidemic.Future DirectionsOngoing research is advancing our understanding of addictive pathways and biochemistry, as well as the identification of biomarkers to recognize which patients are at greater risk for developing addictive disorders (3). The development of opioid formulations that are tamper resistant and the development of pro-drugs might further reduce and deter abuse of prescription opioids (4). Dr. Volkow concluded by challenging physicians everywhere to address pain with more than their prescription pads. She asked that we become advocates for change and build awareness and provide education.Dr. Patel is a PGY-3 Resident Physician in the Department of Psychiatry, University of Connecticut, Farmington, Conn. Amit Mistry, M.D., is a PGY-2 Resident Physician in the Department of Psychiatry, University of Oklahoma, Oklahoma City, Okla.The authors thank Dr. Nora Volkow for her continued work in the field of addiction psychiatry.

Hypoxia-activated prodrugs in the treatment of advanced pancreatic adenocarcinoma.

Pancreatic cancer is an aggressive malignancy with poor survival and high mortality rate with 250 000 deaths per year worldwide. The unique pancreatic cancer microenvironment serves as a major obstacle in the effective treatment of this malignancy. The microenvironment consists not only of pancreatic ductal adenocarcinoma cells but also comprises cells of pancreatic cancer stellate, vascular, and immune origin combined with a dense extracellular matrix containing collagen. The aforementioned pathology leads to an increased intratumor pressure combined with an erratic vascular proliferation within the tumor causing hypoxia and decreased drug delivery. This has led both scientists and clinicians to develop and study drugs with unique mechanisms of action to target the pancreatic cancer microenvironment. Herein, we discuss the pancreatic cancer hypoxic microenvironment, development of hypoxia-activated prodrugs, and results of trials utilizing those drugs to target pancreatic cancer.

Targeting a Targeted Drug: An Approach Toward Hypoxia-Activatable Tyrosine Kinase Inhibitor Prodrugs.

Tyrosine kinase inhibitors (TKIs), which have revolutionized cancer therapy over the past 15 years, are limited in their clinical application due to serious side effects. Therefore, we converted two approved TKIs (sunitinib and erlotinib) into 2-nitroimidazole-based hypoxia-activatable prodrugs. Kinetics studies showed very different stabilities over 24 h; however, fast reductive activation via E. coli nitroreductase could be confirmed for both panels. The anticancer activity and signaling inhibition of the compounds against various human cancer cell lines were evaluated in cell culture. These data, together with molecular docking simulations, revealed distinct differences in the impact of structural modifications on drug binding to the enzymes: whereas the catalytic pocket of the epidermal growth factor receptor (EGFR) accepted all new erlotinib derivatives, the vascular endothelial growth factor receptor (VEGFR)-inhibitory potential in the case of the sunitinib prodrugs was dramatically diminished by derivatization. In line, hypoxia dependency of ERK signaling inhibition was observed with the sunitinib prodrugs, while oxygen levels had no impact on the activity of the erlotinib derivatives. Overall, proof of principle could be shown for this concept, and the results obtained are an important basis for the future development of tyrosine kinase inhibitor prodrugs.

Enhancement of Curcumin Bioavailability Via the Prodrug Approach: Challenges and Prospects.

Curcumin is a natural product with many interesting pharmacological properties. However, these are offset by the particularly poor biopharmaceutical properties. The oral bioavailability of curcumin in humans is very low, mainly due to low solubility, poor stability, and extensive metabolism. This has led to multiple approaches to improve bioavailability, including administration of curcumin with metabolism inhibitors, formulation into nanoparticles, modification of the curcumin structure, and development of curcumin prodrugs. In this paper, we focus on the pharmacokinetic outcomes of these approaches. Pharmacokinetic parameters of curcumin after release from prodrugs are dependent on the linker between curcumin and the promoiety, and the release itself may depend on the physiological and enzymatic environment at the site of cleavage. This is an area in which more data are required for rational design of improved linkers. Cytotoxicity of curcumin prodrugs seems to correlate well with cellular uptake in vitro, but the in vivo relevance is uncertain. We conclude that improved experimental and theoretical models of absorption of curcumin prodrugs, development of accurate analytical methods for simultaneous measurement of plasma levels of prodrug and released curcumin, and acquisition of more pharmacokinetic data in animal models for dose prediction in humans are required to facilitate movement of curcumin prodrugs into clinical trials.

Design, Synthesis, and Bioactivation of O-Glycosylated Prodrugs of the Natural Nitric Oxide Precursor N(ω)-Hydroxy-l-arginine.

Naturally occurring N(ω)-hydroxy-l-arginine (NOHA, 1) is the best substrate of NO synthases (NOS). The development of stable and bioavailable prodrugs would provide a pharmacologically valuable strategy for the treatment of cardiovascular diseases that are associated with endothelial dysfunction. To improve NOHAs druglike properties, we demonstrate that O-substitution by (glycosylic) acetal formation greatly increased the chemical stability of the hydroxyguanidine moiety and provided a nontoxic group that could be easily bioactivated by glycosidases. A straightforward synthetic concept was devised and afforded a series of diversely substituted prodrugs by O-conjugation of the hydroxyguanidine moiety with different monosaccharides. Systematic exploration of their bioactivation profile revealed that glucose-based prodrugs were more efficiently bioactivated than their galactose counterparts. NOS-dependent cytosolic NO release was quantified by automated fluorescence microscopy in a cell-based assay with murine macrophages. Glucose-based prodrugs performed particularly well and delivered cellular NO levels comparable to 1, demonstrating proof-of-concept.

Development and characterization of a long-acting nanoformulated abacavir prodrug.

A myristoylated abacavir (ABC) prodrug was synthesized to extend drug half-life and bioavailability. Myristoylated ABC (MABC) was made by esterifying myristic acid to the drug's 5-hydroxy-cyclopentene group. Chemical composition, antiretroviral activity, cell uptake and retention and cellular trafficking of free MABC and poloxamer nanoformulations of MABC were assessed by proton nuclear magnetic resonance and tested in human monocyte-derived macrophages. Pharmacokinetics of ABC and nanoformulated MABC were evaluated after intramuscular injection into mice. MABC antiretroviral activity in monocyte-derived macrophages was comparable to native drug. Encasement of MABC into poloxamer nanoparticles extended drug bioavailability for 2 weeks. MABC synthesis and encasement in polymeric nanoformulations improved intracellular drug accumulation and demonstrate translational potential as part of a long-acting antiretroviral regimen.

Polysaccharide-based materials in macromolecular prodrug design and development

This review summarises the recent efforts to engineer macromolecular prodrugs (MPDs) based on polysaccharidal materials. Polysaccharidal materials are of utmost importance to design and develop MPDs of non-steroidal anti-inflammatory drugs, antibiotics, anti-viral and anti-cancer drugs, etc. Covalent drug loading capabilities of the polysaccharidal materials are thoroughly discussed. In order to successfully transform drugs into prodrugs using polysaccharidal materials, present review details different syntheses strategies which are being applied to design pharmaceutically viable MPDs. Herein, we also reported the collection of polysaccharidal materials which are being widely spun in to MPDs of several classes of drugs and their applications. Merits and demerits of polysaccharide biomaterials for MPDs are critically discussed. Cellulose ether derivatives are newly introduced materials attracting the vigil eye of researchers working in MPD design for potential therapeutic applications. Special emphasis will be given to amphiphilic materials, i.e. MPDs, which self-assemble at solvent interfaces into nanorods, nanoparticles (NPs), nanowires, etc. Furthermore, the stability of MPDs at elevated conditions of temperature is discussed to gain information about their storage properties. We highlighted thrust areas in polysaccharidal materials-based research and development of MPDs.

Chronic hepatitis B: standard of therapy and perspectives

Infection with the hepatitis B virus (HBV) has much diminished in Italy in the last 25 years; at present, all Italian nationals aged under 36 years are protected from HBV by vaccinal immunity. The problem of the infection has shifted to the immigrants from countries where HBV is still endemic; in this population the prevalence of the infection is high, up to 10% of the immigrants. In the next 5 years the prevalence of HBV is bound to further diminish in the domestic population, for the increment of the age of the subjects protected by mandatory HBV vaccination and for the natural exhaustion of the elderly cohorts of HBsAg carriers which represent the last domestic reservoir of the infection. Most likely, instead, the problem in immigrants will become more important, forcing new strategies to the approach and containment of HBV. Therapy of hepatitis B is not satisfactory; it allows the control of HBV replication and related disease but is not capable of clearing the virus; eradication of the HBsAg is achieved only in few patients. The future target are therapies aimed at eradicating the HBV, not only at containing its replication and disease expression. A miriad new drugs acting directly against functions necessary to the life cycle of the HBV are under study; it is unlikely, however, that they will enter clinical trials in the few years. More promising in the short term, it is the development of prodrugs of antivirals currently in use, of which tenofovir alafenamide (TAF), the prodrug of tenofovir, is the prototype, entering soon into therapeutic routine.

Ruthenium Complexes: An Emerging Ground to the Development of Metallopharmaceuticals for Cancer Therapy.

GLOBOCAN 2012 estimates 14.1 million new cancer cases and 8.2 million cancer-related deaths worldwide. Cancer is rapidly becoming a major public health concern in India as well, with the number of new cancer cases anticipated to double within the next 20 years. The percentage of currently approved metallodrugs is very low, in contrast to the majority of drugs available as organic compounds. The search for alternative drugs to cisplatin, carboplatin and other derivatives is highly needed due to their severe side effects including nephrotoxicity and neurotoxicity. Ruthenium, among other transition metal complexes appears to be a possible candidate for cancer therapy in the near future. The most significant rationale is ruthenium's octahedral chemistry and greater propensity to undergo redox reactions. The hypoxic environment of tumors favors the reduction of inert ruthenium (III) to active ruthenium (II) which opens new prospects for the development of novel prodrugs. Although studies suggest that ruthenium complexes penetrate well within the tumor cells and bind effectively to DNA, its binding to proteins is not very well explained. Ruthenium complexes are presently receiving great attention in the fields of biological, pharmaceutical and medicinal chemistry as anticancer agents. This review poses a comprehensive overview of the studies on competent anticancer ruthenium complexes and the role of these metal complexes in relation to their anticancer properties as well as those under clinical trials.

Development of octreotide-conjugated polymeric prodrug of bufalin for targeted delivery to somatostatin receptor 2 overexpressing breast cancer in vitro and in vivo.

BackgroundDevelopment of polymeric prodrugs of small molecular anticancer drugs has become one of the most promising strategies to overcome the intrinsic shortcomings of small molecular anticancer drugs and improve their anticancer performance.Materials and methodsIn the current work, we fabricated a novel octreotide (Oct)-modified esterase-sensitive tumor-targeting polymeric prodrug of bufalin (BUF) and explored its anticancer performance against somatostatin receptor 2 overexpressing breast cancer.ResultsThe obtained tumor-targeting polymeric prodrug of BUF, P(oligo[ethylene glycol] monomethyl ether methacrylate [OEGMA]-co-BUF-co-Oct), showed a nanosize dimension and controlled drug release features in the presence of esterase. It was demonstrated by in vitro experiment that P(OEGMA-co-BUF-co-Oct) showed enhanced cytotoxicity, cellular uptake, and apoptosis in comparison with those of free BUF. In vivo experiment further revealed the improved accumulation of drugs in tumor tissues and enhanced anticancer performance of P(OEGMA-co-BUF-co-Oct).ConclusionTaken together, this study indicated that polymeric prodrug of BUF holds promising potential toward the treatment of somatostatin receptor 2 overexpressing breast cancer.

Design and synthesis of peptide conjugates of phosphoramide mustard as prodrugs activated by prostate-specific antigen

A series of Glutaryl-Hyp-Ala-Ser-Chg-Gln-4-aminobenzyl phosphoramide mustard conjugates (1a–e) was designed and synthesized as potential prodrugs for site-specific activation by PSA in prostate cancer cells. All conjugates were found to be substrates of PSA with cleavage occurring between Gln and the para-aminobenzyl (PAB) linker. Structure–activity relationship studies on these conjugates indicated that introduction of electron-withdrawing fluorine(s) on the phenyl ring in the PAB linker uniformly improved the chemical stability of the conjugates while the position of substitution affected differently the self-immolative process of conjugates upon proteolysis. Introduction of a fluorine at ortho position to benzylic phosphoramide as in 1b results in better stability of the conjugate prior to activation while maintaining its antiproliferative activity upon activation by PSA. The conjugate 1b with 2-fluoro substitution was identified as a promising lead for further evaluation and optimization in the development of prostate cancer-targeted prodrugs.

Enhanced Antitumor Activity of Monophosphate Ester Prodrugs of Gemcitabine: In Vitro and In Vivo Evaluation

The prodrug strategy has been explored frequently for a number of marked drugs to obtain better pharmaceutical properties and efficacy and safety profiles. For gemcitabine, a nucleoside analog that has been used widely as a chemotherapeutic agent for the treatment of a variety of cancers, the protection of the amino group from extensive deamination and increase of permeability have been used for oral prodrug development. In the present study, several novel and proprietary monophosphate ester prodrugs of gemcitabine representing different “tail” structures were evaluated for their antiproliferation activities in various tumor cell lines. As compared to LY2334737, a prototype oral prodrug of gemcitabine, the monophosphate ester prodrugs exhibited superior in vitro antiproliferation activity. Among those, compound-3 emerged as a promising prodrug candidate. Data revealed that cellular concentrations of compound-3 were correlated well with its antiproliferation activity and its cellular uptake did not involve human equilibrative nucleoside transporter, suggesting a potential to treat gemcitabine resistant tumors. Compound-3 demonstrated equal or better antitumor efficacy after oral administration as compared to intraperitoneally injected gemcitabine. Taken together, compound-3 has the potential for further development as an orally active antitumor agent.