Triphenylmethanol Conjugates of Triptorelin as Cell-Penetrating Anti-Cancer Prodrugs

Some Triptorelin® (TRP) conjugates of triphenylmethanol derivatives (TPMs) with optimized hydrophobicity were synthesized by reacting 2-substituted methoxy benzenes with 1,3,5-trioxane, followed by the conjugation with TRP and sebacic acid to produce TRP-TPMs derivatives. Comparative antiproliferative assays between TRP-TPMs conjugates and the corresponding non-covalent physical mixtures of the TPMs derivatives and TRP were used to treat human acute lymphoblastic leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3) and mouse preadipocytes (3T3-L1) cells. TRP-TPMs conjugates at the 50 μM inhibited cell proliferation in CCRF-CEM, SK-OV-3 and 3T3-L1 cells by 21% - 37%, 24% - 73%, 37% - 56%, respectively following incubation for 72 h. These findings indicate that TRP-TPMs derivatives have the potential to enhance the biological activity of TRP.

Prodrugs incorporated into nanotechnology-based drug delivery systems for possible improvement in bioavailability of ocular drugs delivery

Numerous systems have been designed during the past three decades to improve bioavailability of ophthalmic drug delivery,including:ocular prodrugs and nanotechnology-based drug delivery system.The former can improve the efficacy of ocular drug via enhancing corneal penetration of ocular drugs,prolonging their duration of action and/or reducing the systemic side-effects,unfortunately,some characteristics of the pro-drugs,such as poorly aqueous stability,poorly aqueous solubility and severe eye irritation probably,limit their clinical practice and cannot be ignored.As we all know,nanotech-nology for ocular drug delivery can carry poorly soluble drugs,protect the encapsulated molecules from hydrolysis,control the rate of drug delivery and prolong the precorneal retention of drugs.All of these merits may solve the problems in the utilization of ocular prodrugs and increase the bioavailability of ocular drug delivery.By reviewing recent ad-vances of prodrugs and nanostructures in ocular drug delivery,this paper focus specifically on the promising prospects of nanocarriers overcoming the drawbacks of prodrugs for ophthalmic drug delivery by precorneal routes.

Synthesis and Evaluation of Glyceride Prodrugs of Naproxen

The glyceride ester derivatives 6a and 6b were prepared by reacting 1,2,3-trihydroxy propane 1,3-dipalmitate/stearate with (S)-naproxen as potential prodrugs. The synthesis was achieved successfully with the aid of N,N’-dicyclohexyl- carbodiimide. These prodrugs were evaluated for anti inflammatory, analgesic and gastroprotective activity. It was found that prodrugs 6a and 6b showed less irritation to gastric mucosa as indicated by ulcer index. The synthesized glyceride esters were found to possess good pharmacological profile as shown by results of anti inflammatory and analgesic activity. The aqueous studies were performed in order to ensure the release of prodrugs. Both prodrugs were found to stable at acidic pH while undergoes hydrolysis at pH 7.4. These findings suggest that the glyceride prodrugs 6a and 6b might be used as potential biolabile derivatives.

Investigation of mitigating effect of colon-specific prodrugs of boswellic acid on 2,4,6-trinitrobenzene sulfonic acidinduced colitis in Wistar rats: Design, kinetics and biological evaluation

AIM To develop a colon-targeting bioreversible delivery system for β-boswellic acid(BBA) and explore utility of its prodrugs in 2,4,6-trinitrobenzene sulfonic acid(TNBS)-induced colitis in rats.METHODS Synthesis of 4 co-drugs of BBA with essential amino acids was achieved by CDI coupling, followed by their spectral characterization. In vitro kinetics were studied by HPLC in aqueous buffers, homogenates of gastrointestinal tract and fecal matter. In vivo kinetic studies were performed in Wistar rat plasma, urine and feces. The prodrugs were screened in TNBS-induced colitis modeled Wistar rats. Statistical significance was assumed at P < 0.05, P < 0.01, P < 0.001 when compared with disease controls using one-way and two-way ANOVAs.RESULTS Prodrugs were stable in 0.05 mol/L HCl buffer(p H 1.2) and stomach homogenates. Negligible hydrolysis was observed in phosphate buffer and intestinal homogenates. Substantial release(55%-72% and 68%-86%) of BBA was achieved in rat fecal matter and homogenates of colon. In vivo studies of BBA with L-tryptophan(BT) authenticated colon-specific release of BBA. But, surprisingly substantial concentration of BBA was seen to reach the systemic circulation due to probable absorption through colonic mucosa. Sitespecifically enhanced bioavailability of BBA could be achieved in colon, which resulted in demonstration of significant mitigating effect on TNBS-induced colitis in rats without inducing any adverse effects on stomach, liver and pancreas. Prodrug of BT was found to be 1.7%(P < 0.001) superior than sulfasalazine in reducing the inflammation to colon among all prodrugs tested. CONCLUSION The outcome of this study strongly suggests that these prodrugs might have dual applicability to inflammatory bowel disease and chronotherapy of rheumatoid arthritis.

Ocular prodrugs: Attributes and challenges

Ocular drug delivery is one of the most attention-grabbing and challenging endeavors among the numerous existing drug delivery systems.From a drug delivery point of view,eye is an intricate organ to investigate and explore.In spite of many limitations,advancements have been made with the intention of improving the residence time or permeation of the drug in the ocular region.Poor bioavailability of topically administered drugs is the major issue pertaining to ocular drug delivery.Several efforts have been made towards improving precorneal residence time and corneal penetration,e.g.iontophoresis,prodrugs and ionpairing,etc.Prodrug approach(chemical approach)has been explored by the formulation scientists to optimize the physicochemical and biochemical properties of drug molecules for improving ocular bioavailability.Formulation of ocular prodrugs is a challenging task as they should exhibit optimum chemical stability as well as enzymatic liability so that they are converted into parent drug after administration at the desired pace.This review will encompass the concept of derivatization and recent academic and industrial advancements in the field of ocular prodrugs.The progression in prodrug designing holds a potential future for ophthalmic drug delivery.

Synthesis and Stability of Hydroxyfasudil Derivatives as Prodrugs

Fasudil(HA-1077) is the first small-molecule inhibitor of Rho-kinase and has been employed for clinical treatment of cerebral vasospasm.Hydroxyfasudil,as a metabolite of fasudil,exhibited better activity than fasudil.However,it also suffered from quick metabolisation,weak lipotropy and worse penetration of the blood-brain barrier.Thus,some hydroxyfasudil derivatives such as hydroxyfasudil acetate,hydroxyfasudil phosphate and 1-methoxyfasudil as the prodrugs of hydroxyfasudil were designed and synthesised.Meanwhile,the stability of these three compounds was also investigated.Furthermore,the reason and mechanism of hydrolysis of these compounds were discussed.This work could provide a useful guide for future research.

Triphenylmethanol Conjugates of Triptorelin as Anti-Lipid Peroxidation Prodrugs

Antioxidants are substances that can prevent or slow damage to cells caused by free radicals, unstable molecules that the body produces as a reaction to environmental and other pressures. Free radicals may play a role in heart disease, cancer and other diseases. If the body cannot process and remove free radicals efficiently, oxidative stress can result. This can harm cells and body function. Free radicals are also known as reactive oxygen species (ROS). In this research, Triptorelin&#174;(TRP) conjugates of triphenylmethanol derivatives (TPMs) were synthesized to evaluate their in vitro lipid peroxidation potency. Comparative lipid peroxidation assays between TRP-TPMs conjugates and the corresponding TPMs derivatives were measured using thiobarbituric reactive substance (TBARS) in a dose- and time-dependent manner following the Fenton’s pathway. Overall, TBARS decreased between 20% - 30% for the treated samples of synthesized conjugates compared to their respective control physical mixtures. These data suggest that TRP-TPMs derivatives can be used to improve the biological activity of TRP.

Synthesis and Cytotoxic Activity of Novel Water-soluble Prodrugs of Combretastatin A-4

Novel water-soluble prodrugs of combretastatin A-4 （5-8） were synthesized and evaluated for their in vitro cytotoxicity against lung carcinoma A549. Compound 5, bearing phosphoryl choline （PC） moiety, showed 90% inhibition at 32 ktg/mL concentration after 24 h. The findings showed the PC derivative would be a promising candidate for the development of new water-soluble prodrug of cytotoxic combretastatin A-4,

Design, synthesis and in vitro evaluation of L-amino acid esters prodrugs of acyclic nucleoside phosphonates as anti-HBV agent

A series of novel L-amino acid esters prodrugs of acyclic nucleoside phosphonates was synthesized and their anti-HBV activity was evaluated in HepG2 2.2.15 cells. Compound 1d exhibited more potent anti-HBV activity and lower cytotoxicity than those of adefovir dipivoxil with EC50 and CC50 values of 0.207 μmol/L and 2530 μmol/L, respectively.

Preparation of Curcumin Prodrugs and Their in Vitro Anti-tumor Activities

The curcumin prodrugs, which could be selectively activated in tumor cells, were prepared to establish a basis for the targeted chemotherapy for cancer. On the basis of the molecular structure of curcumin, the N-maleoyl-L-valine-curcumin （NVC）, N-maleoyl- glycine-curcumin （NGC） were chemically synthesized and identified by IR and NMR spectroscopy. After treatment with these two prodrugs for 6--24 h, the rates of growth inhibition on human bladder cancer EJ cells and renal tubular epithelial （HKC） cells were detected by MTT colorimetry. Our results showed that after the treatment with 20 μmol/L--40 μmol/L NVC and NGC for 6--24 h, the growth inhibitory effects on EJ cells were 6.71%-65.13 % （P〈0.05）, 10. 96 %-73.01 % （p〈0. 05）, respectively, in both dose- and time-dependent manners. When compared with the curcumin of same concentrations, the growth inhibitory effects of these two prodrugs on HKC cells were significantly decreased （P〈0.01）. It is concluded that activation of curcumin prodrugs via hydrolysis functions of cellular esterase could inhibit the growth activities of tumor cells, and reduce the side effects on normal diploid cells. This provided a novel strategy for further exploration of tumor targeted chemotherapeutic drugs.

Synthesis, characterization and in vivo evaluation of honokiol bisphosphate prodrugs protects against rats’ brain ischemia-reperfusion injury

Honokiol(HK)usage is greatly restricted by its poor aqueous solubility and limited oral bioavailability.We synthesized and characterized a novel phosphate prodrug of honokiol(HKP)for in vitro and in vivo use.HKP greatly enhanced the aqueous solubility of HK(127.54±15.53 mg/ml)and the stability in buffer solution was sufficient for intravenous administration.The enzymatic hydrolysis of HKP to HK was extremely rapid in vitro(T 1/2=8.9±2.11 s).Pharmacokinetics studies demonstrated that after intravenous administration of HKP(32 mg/kg),HKP was converted rapidly to HK with a time to reach the maximum plasma concentration of^5 min.The prodrug HKP achieved an improved T 1/2(7.97±1.30 h)and terminal volume of distribution(26.02±6.04 ml/kg)compared with direct injection of the equimolar parent drug(0.66±0.01 h)and(2.90±0.342 ml/kg),respectively.Furthermore,oral administration of HKP showed rapid and improved absorption compared with the parent drug.HKP was confirmed to maintain the bioactivity of the parent drug for ameliorating ischemia-reperfusion injury by decreasing brain infarction and improving neurologic function.Taken together,HKP is a potentially useful aqueous-soluble prodrug with improved pharmacokinetic properties which may merit further development as a potential drug candidate.

Balancing efficacy and safety of doxorubicin-loaded albumin nanoparticles utilizing pH-sensitive doxorubicin-fatty acid prodrugs

Albumin nanoparticles(ANPs)offer unique advantages for antitumor drug delivery system,including non-immunogenicity and inherent tumor-targeting capacity.At present,only a few products,such as ABRAXANE®and FYARRO™,have been approved for clinical applications.The poor affinity of doxorubicin(DOX)for albumin,coupled with its numerous severe adverse reactions,poses challenges in the fabrication of desirable albumin nanoparticles loaded with DOX.In this study,we developed prodrugs by conjugating fatty acids of varying lengths with DOX.Our aim was to investigate the balance between efficacy and safety through the selection of appropriate modules.We synthesized five pH-sensitive doxorubicin-fatty acid prodrugs.Compared to free DOX,all DOX prodrug ANPs exhibited a uniform size distribution with desirable sizes of 150 nm.Additionally,DOX prodrugs with hydrazone bonds remained intact in blood circulation while releasing DOX within tumor cells.Significantly,the characteristics of prodrug ANPs were considerably influenced by the length of fatty acids,impacting their in vivo pharmacokinetics,antitumor effectiveness and tumor accumulation.This research offers a detailed understanding of the length of fatty acid influence on DOX-fatty acid prodrug-based ANPs,and it builds a good platform for creating ANPs which prioritize high drug loading,high efficiency,and minimal side effects.

Hydrogen sulfide prodrugs—a review

Hydrogen sul fi de(H_2S) is recognized as one of three gasotransmitters together with nitric oxide(NO) and carbon monoxide(CO). As a signaling molecule, H_2S plays an important role in physiology and shows great potential in pharmaceutical applications. Along this line, there is a need for the development of H_2S prodrugs for various reasons. In this review, we summarize different H_2S prodrugs, their chemical properties, and some of their potential therapeutic applications.

Enzyme-mediated hydrolytic activation of prodrugs

Prodrug design is an important part of drug discovery.Prodrugs can offer many advantages over parent drugs such as increased solubility,enhanced stability,improved bioavailability,reduced side effects,and better selectivity.Many prodrugs have been used successfully in the clinic;examples include oseltamivir in anti-influenza therapy,enalapril in anti-hypertension therapy,capecitabine in cancer therapy,and omeprazole in the treatment of peptic ulcer.A key step in prodrug design is the incorporation of an activation mechanism that can convert the prodrug into the active species in an efficient and/or controlled manner to meet the needs of a given medical application.Prodrug activation can be achieved through enzyme-mediated hydrolytic or oxidoreductive processes while activation of some prodrugs may proceed through pure chemical nonenzymatic processes.This review focuses on the hydrolytic enzymes that have been used in prodrug activation,including transferases,hydrolases,and lyases.

Prodrugs of hydrogen sulfide and related sulfur species: recent development

Hydrogen sulfide(H2S) is commonly referred to as the third gasotransmitter with firmly established physiological roles. Prodrug approaches have been broadly applied to deliver H2S for various applications and mechanistic studies. Since S-persulfidation and glutathionylation are known to be important in cellular signaling by sulfur species, there have been interests in developing donors of persulfide and glutathione persulfide as well. In this review, we discuss the recent development in area of prodrugs for various sulfur species.

Acid-sensitive PEGylated cabazitaxel prodrugs for antitumor therapy

Although the antitumor drug cabazitaxel shows great therapeutic potential,its high toxicity and poor water solubility limit its utility.However,the use of stimuli-responsive prodrugs is a promising strategy for overcoming these limitations.Herein,we report the synthesis of two highly water soluble,acidsensitive PEGylated acyclic-ketal-linked cabazitaxel prodrugs(PKCs)with improved antitumor efficacy.In an acidic tumor microenvironment,the PKCs hydrolyzed rapidly to release the native drug,whereas they were stable in the normal physiological environment.Compared with cabazitaxel injection,the PKCs had much higher maximum tolerated doses:and in an MDA-MB-231 subcutaneous xenograft nude mouse model,the PKCs showed better antitumor efficacy and safety than cabazitaxel injection.The prodrug strategy reported herein could be useful for the development of other water soluble,acidsensitive prodrugs with improved efficacy.

Facile preparation of pH-responsive PEGylated prodrugs for activated intracellular drug delivery

PEGylated prodrug,covalent attaching polyethylene glycol(PEG) polymer chains to therapeutic drugs,is one of the most promising techniques to improve the water-solubility,stability,and therapeutic effect of drugs.In this study,three PEGylated acid-sensitive prodrugs DOX-PEG-DOX with different molecular weights,were prepared via Schiff-base reaction between aldehyde-modified PEG and the amino groups of doxorubicin(DOX).This kind of amphiphilic polymeric prodrug could be self-assemble into nanoparticles in aqueous solution.The average particle size and morphologies of the prodrug nanoparticles under different pH conditions were observed by dynamic light scattering(DLS) and transmission electron microscopy(TEM),re s pectively.It turned out that the nanoparticles could be kept stable in the physiological environment,but degraded in acidic medium.Subsequently,we also investigated in vitro drug release behavior and found that the prodrug had acid-sensitive property.The cytotoxicity and intracellular uptake assays revealed that the prodrugs could rapidly internalized by HeLa or HepG2 cells to release DOX and effectively inhibited the proliferation of the tumor cells,which have the potential for use in cancer therapy.

Design,synthesis and in vitro evaluation of mono(2,2,2-trifluoroethyl)esters,mono L-amino acid ester prodrugs of acyclic nucleoside phosphonates as anti-HBV agents

A series of novel mono（2,2,2-trifluoroethyl） esters,mono L-amino acid ester prodrugs of acyclic nucleoside phosphonates was synthesized and their in vitro anti-HBVactivity was evaluated in HepG 2 2.2.15 cells.Compound 1d exhibited more potent anti-HBV activity and lower cytotoxicity than those of adefovir dipivoxil and alamifovir（MCC-478） with EC_（50） and CC_（50） values of 0.01μmol/L and 8000μmol/L respectively.

Hydrogen Sulfide-Specific and NIR-Light-Controllable Synergistic Activation of Fluorescent Theranostic Prodrugs for Imaging-Guided Chemo- Photothermal Cancer Therapy

Theranostic prodrugs are promising for cancer medicine;however,the inability to activate these systems exclusively at the desired tumor location compromises the specificity and efficacy of cancer treatment.Here,we developed a fluorescent theranostic nanoprodrug with synergistic hydrogen-sulfidespecific and near-infrared(NIR)-light-controllable activation for imaging-guided chemo-photothermal cancer therapy.This nanoprodrug system was fabricated by the inclusion of hydrogen sulfide(H2S)-activatable small molecule to the theranostic prodrug and a photothermal transducer in the interior of a NIR-light-responsive container.

Self-assembled small molecular weight hydrogels of prodrugs

Molecular self-assembly is very ordinary phenomenon in the biological process such as protein folding,DNA encoding and etc.Inspired by this inherent biological process,nanostructure such as nanofibers,nanosphere,and so on formed by the therapeutic agents and its derivatives that can further self-assemble into supramolecular hydrogels have attained considerable attentions in the field of drug delivery due to its favorable features such as high and precise drug payload,carrier-free and excellent biocompatibility.Additionally,the prodrug hydrogelator can be rationally designed to fine-tune over its drug release behavior and degradation in response to various biological stimulus（temperature,p H,ionic strength and etc.）.This review summarized and discussed the recent advancement in the self-assembled small molecular weight hydrogels of prodrugs.