Succinate Ester Research Articles

Comparative analysis of the crystal structures of hydrates and sodium salts of monensin and its new C-26 succinate ester

Monensin succinate ester hydrate (2-H2O) has been synthesized by the succinylation of C-26 hydroxyl group of monensin (1) using a simple reaction with succinic anhydride. Additionally, the sodium salt (2-Na) of monensin succinate ester has been obtained. Molecular structures of both compounds (2-H2O and 2-Na) were studied using X-ray diffraction of single crystals and spectroscopic methods. According the crystallographic studies of 2-H2O and 2-Na, the molecules are held together as dimers linked by the centrosymmetric pairs of intermolecular hydrogen bonds between the carboxylic groups. The crystal structures of compounds 2-H2O and 2-Na are compared to those of the known monensin acid hydrate (1-H2O) and 1:1 inclusion complex of monensin A sodium salt with acetonitrile (1-Na-CH3CN) and that of newly obtained monensin sodium salt monohydrate (1-Na-H2O). Comparison of these structures showed a significant impact of C-26 succinate ester moiety on the coordination of the Na+ cation and hydrogen bond.

Hypersensitivity to intravenous succinate corticosteroids in patients with nonsteroidal anti-inflammatory drug-exacerbated respiratory disease.

Although there are many case reports of asthma exacerbations with intravenous corticosteroids, especially hydrocortisone succinate, in nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD), the frequency and mechanism remain unclear. We hypothesized that N-ERD patients are potentially hypersensitive to succinates, especially succinate corticosteroids, based on the results of previous provocation studies and considered specific mechanisms. The objective of this study was to determine the frequency and mechanism of succinate corticosteroids hypersensitivity in patients with N-ERD. Eleven patients with stable, moderate to severe N-ERD were tested with hydrocortisone sodium succinate (HCs), hydrocortisone sodium phosphate (HCp), methylprednisolone sodium succinate (MPSLs), prednisolone sodium succinate (PSLs), and chloramphenicol sodium succinate (CPs, without a steroidal chemical structure) at doses below the normal dose through intravenous administration using a single-blind test. As a comparison, seven patients with aspirin-tolerant asthma (ATA) also underwent an intravenous provocation test of HCs. The positive intravenous provocation test rates of HCs 100-500 mg, HCp 500 mg, MPSLs 80 mg, PSLs 20 mg, and CPs 500 mg in N-ERD patients were 82% (9/11), 9% (1/11), 50% (5/10), 33% (1/3), and 86% (6/7), respectively. Most positive reactions began with a severe cough within 5 min of intravenous injection. The course of these hypersensitivity symptoms differed from those seen with the usual aspirin challenge test. The HCs 100-500 mg intravenous test was negative in all seven patients with ATA. In conclusion, patients with N-ERD have high rates of potential hypersensitivity to the succinate ester structure, which is not linked to the corticosteroid structure, but to the succinate ester structure. We hypothesized that the mechanism of hypersensitivity observed during rapid intravenous administration of succinate corticosteroids is mast cell activation via succinate receptor stimulation, rather than due to the corticosteroid itself.

Redox-Responsive Hyaluronic Acid-Tacrolimus Conjugate: Synthesis, Characterization, and In Vitro Immunosuppressive Activity.

A redox-responsive macromolecular prodrug of tacrolimus, HA-ss-Tac, was constructed by conjugation of tacrolimus (TAC, FK506) through its succinate ester to cystamine-modified hyaluronic acid (HA-Cys), and its physicochemical properties and immunosuppressive activity were studied. The synthesized HA-ss-TAC was determined to contain 8% of chemically loaded TAC with significantly enhanced water solubility. The release study showed a sustained release of drug through slow degradation of linker-drug bonds. In vitro inhibition of proliferation of T- and B-lymphocytes was almost comparable to that of TAC, implying that the biologically active compound could be released from the conjugate. The polymeric prodrug lacks obvious cytotoxicity on Raw 264.7 macrophages and significantly suppressed the production of inflammatory cytokines IL-2 and IL-1β by LPS-activated cells. Additionally, the cellular uptake study of the FITC-labeled conjugate confirmed the HA receptor-mediated internalization of the conjugate into targeted cells, thus avoiding systemic side effects. Taken together, the HA-ss-TAC prodrug could be an optimal prodrug for intravenous administration based on this preliminary data and can be expected to have improved therapeutic efficacy.

Biotechnological Application of Cutinase: A Powerful Tool in Synthetic Biology

Cutinases (EC 3.1.1.74) are widely distributed in fungi, bacteria and plants with diversified structures and properties. Besides acting on the natural substrate cutin, cutinases are the first line of natural biocatalysts to hydrolyze artificial polyesters and toxic xenobiotics such as polyethylene terephthalate (PET), polycaprolactone (PCL), polylactic acid (PLA), polyhydroxybutyl succinate (PBS), phthalate and malathion esters. Moreover, cutinases can act as promising stereoselective catalysts in esterification and transesterification reactions and present better selectivities than lipases. These pioneering studies indicate that the biotechnological application of cutinase as a powerful tool in synthetic biology deserves further investigation, for both degradation and biosynthesis towards a broader range of ester bond-containing substrates. This review summarizes the classifications and properties of cutinases from different sources and insights into the structure–function relationship of different cutinases. It also highlights the uniqueness and advantages of representative cutinases in biodegradation and biosynthesis, and then prospects the future application of natural and engineered cutinases in synthetic biology.

Batch-to-Continuous transition in the specialty chemicals Industry: Impact of operational differences on the production of dispersants

Specialty chemicals are typically produced in large-volume batch reactors characterized by straightforward operation but limited efficiency. Process intensification via transition from batch to continuous operation offers the prospect of strong improvements over current state-of-the-art in energy intensity, process safety, capital cost, and physical footprint. The present study investigated the production of two dispersants to demonstrate the viability of batch-to-continuous transition for the specialty chemicals industry: Succinate ester dispersants, formed in a one-step addition reaction, and succinimide dispersants, formed via a two-step reaction with water as by-product. While the ester process showed identical dispersant yields in batch and continuous operation under identical conditions, the succinimide process produced significantly higher yields in the batch compared to the continuous reactor. This could be traced back to an operational difference between these processes: In the batch process, the by-product water is continuously removed from the reactive mixture while purging the reactor head space, rendering the dehydration step effectively irreversible. In contrast, to prevent steam-induced foaming, the continuous reactor is operated at high-enough pressure to maintain water in the liquid phase. This renders the dehydration step incomplete due to thermodynamic equilibrium limitations. However, the full succinimide product yield could be recovered via subsequent continuous drying using a thin film evaporator. This product was indistinguishable from the batch product and fulfilled commercial specifications. Finally, full reversible reaction kinetics were derived based on the continuous reactor operation. Comparison between batch operation results and reactor modeling predictions indicated that the slow apparent kinetics of the industrial batch process is the result of mass transfer limitations due to slow water evaporation, and not caused by limitations in the intrinsic reaction kinetics.

Methylprednisolone-induced anaphylaxis diagnosed by intradermal skin test: a case report

BackgroundGlucocorticoids rarely cause anaphylaxis. Common methods for the determination of allergens include in vivo skin prick test (SPT) and intradermal skin test (IDST) and the in vitro basophil activation test (BAT). However, to our knowledge, the best strategy for diagnosing glucocorticoid-induced anaphylaxis has not been elucidated.Case presentationA 10-year-old boy was admitted to our hospital because of 2 weeks of fever and arthralgia. He had not been treated with glucocorticoids before, including methylprednisolone (mPSL). He was suspected to have bacterial myositis and was treated with ceftriaxone. However, his symptoms persisted for > 2 weeks. Autoinflammatory arthritis was suspected, and he was treated with mPSL sodium succinate (MPS) pulse therapy (30 mg/kg). After 15 min of mPSL injection, he had wheezing and generalized wheal formation with decreased oxygen saturation. As anaphylaxis was suspected, mPSL was discontinued, and olopatadine and oxygen were administered. The symptoms improved considerably without the use of epinephrine and disappeared in 30 min. One month after discharge, SPT, IDST, and BAT were performed without discontinuing his prescribed oral prednisolone. SPTs for MPS, hydrocortisone sodium succinate (HCS), prednisolone sodium succinate (PSS), dexamethasone sodium phosphate (DSP), and betamethasone sodium phosphate (BSP) were negative. IDSTs for MPS, HCS, and PSS were positive, whereas those for DSP and BSP were negative. By contrast, BATs for MPS, HCS, and PSS were negative. Although glucocorticoid-induced hypersensitivity caused by nonmedicinal ingredients such as lactose, carboxymethylcellulose, polyethylene glycol, and hexylene glycol has been reported; the glucocorticoids tested in this patient did not contain any of these nonmedicinal ingredients. As the glucocorticoids that were positive on IDST share a succinate ester, this might have caused MPS-induced anaphylaxis.ConclusionsWe report the case of MPS-induced anaphylaxis diagnosed by IDST but not BAT. In case reports of glucocorticoid-induced anaphylaxis in the literature, most patients were diagnosed with SPT or IDST. These results suggest that BAT should be considered when IDST and SPT are negative. Further studies are necessary to clarify the best strategy for diagnosing glucocorticoid-induced anaphylaxis.

Conversion of bioplatform molecule, succinic acid to value-added products via esterification over 12-tungstosilicic acid anchored to MCM-22

The model bioplatform molecule succinic acid, via esterification with n-butanol, leads to succinate esters, promising fuel additives and value-added products. In the present article, the potential application of heterogeneous catalyst comprising silicotungstic acid (SiW12) and MCM-22 (SiW12-MCM-22) was exploited for esterification of succinic acid with n-butanol. Performance of the catalyst was examined by carrying out a detailed optimization study, focusing on the synthesis of diester (one of the excellent fuel additives) and kinetic experiments at different reaction time and temperatures. The experimental results exhibit synergistic effect of SiW12 and MCM-22, yielding 97% conversion of acid with 59% selectivity of diester, TON of 1214 and activation energy of 68 kJmol-1. Experiments to demonstrates the effectiveness of High Gravity approach were also performed. The green metrics, atom economy (86.47%) (for desired diester) with E-factor (0.69) were calculated. The catalyst was recovered and used for consecutive three catalytic cycles, exhibiting remarkable regenerative activity to synthesize esters and contribute new routes for industrial scale.

Ameliorated in vitro anticancer efficacy of methotrexate d-\u03b1-Tocopheryl polyethylene glycol 1000 succinate ester against breast cancer cells

BackgroundMethotrexate (MTX), a folate anti-metabolite, has been used widely in the treatment of plenty of malignancies. However, the clinical use is limited because of its poor water solubility (BCS class II drug), nonspecific distribution, drug resistance, short circulation half-life, and toxicity. The objective of the present research was to synthesize the ester prodrug of MTX with d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) and characterize for in vitro anticancer efficacy.ResultsThe FTIR and NMR results revealed the successful synthesis of the prodrug. The assay and saturation solubility of the prodrug is found to be 23 ± 2.5% and 6.7 ± 1.3 mg/mL (MTX equivalent) respectively. The CMC of the prodrug in distilled water at room temperature is found to be 36.9 ± 2.6 μg/mL. The prepared prodrug micelles showed a mean particle size of 166 ± 10 nm (PDI, 0.325 ± 0.09). Further, the TEM results confirmed the self-assembling character of the prodrug into micelles with a nearly spherical shape. The prodrug caused the significantly (p < 0.01) less hemolysis (16.8 ± 1.5%) when compared to plain MTX solution and significantly higher (p < 0.01) in vitro cytotoxicity, cell cycle arresting, and apoptosis against human breast cancer cells (MCF-7 and MDA-MB-231).ConclusionOur study results revealed the remarkable in vitro anticancer activity of MTX following its esterification with TPGS. However, further, in vivo studies are needed to prove its efficacy against different cancers.

Curcumin diethyl disuccinate, a prodrug of curcumin, enhances anti-proliferative effect of curcumin against HepG2 cells via apoptosis induction

Curcumin (Cur) has been reported to have anti-hepatocellular carcinoma activity but its poor oral bioavailability limits its further development as a chemotherapeutic agent. We synthesized previously a succinate ester prodrug of Cur, curcumin diethyl disuccinate (CurDD) with better chemical stability in a buffer solution pH 7.4. Here, we further investigated and compared the cellular transport and anti-proliferative activity against HepG2 cells of CurDD and Cur. Transport of CurDD across the Caco-2 monolayers provided a significantly higher amount of the bioavailable fraction (BF) of Cur with better cytotoxicity against HepG2 cells compared to that of Cur (p < 0.05). Flow cytometric analysis showed that the BF of CurDD shifted the cell fate to early and late apoptosis to a higher extent than that of Cur. The Western blot analysis revealed that CurDD increased Bax protein expression, downregulated Bcl-2 protein, activated caspase-3 and -9 and increased LC3-II protein level in HepG2 cells. Flow cytometric and immunoblotting results suggest that CurDD can induce HepG2 cell death via an apoptotic pathway. We suggest that CurDD can overcome the limitations of Cur in terms of cellular transport with a potential for further extensive in vitro and in vivo studies of anti-hepatocellular carcinoma effects.

Scale-Up Synthesis and In Vivo Anti-Tumor Activity of Curcumin Diethyl Disuccinate, an Ester Prodrug of Curcumin, in HepG2-Xenograft Mice.

Previously, we synthesized curcumin and a succinate ester prodrug of curcumin namely curcumin diethyl disuccinate (CurDD) in the lab scale, which yielded hundred milligrams to few grams of the compounds. CurDD was found to be more stable in a phosphate buffer pH 7.4 and exhibited better cytotoxicity against Caco-2 cells than curcumin. Here, the one-pot syntheses of curcumin and CurDD were scaled up to afford multigram quantities of both compounds for preclinical studies using a 10-L chemical reactor. The key steps for the synthesis of curcumin were the formation of boron-acetylacetone complex and the decomplexation of boron-curcumin complex. The synthesis of CurDD could be achieved via a one-step esterification between curcumin and succinic acid monoethyl ester chloride using 4-(N,N-dimethylamino)pyridine as a catalyst. The synthesized curcumin and CurDD were then investigated and compared for an anti-tumor activity in HepG2-xenograft mice. CurDD could reduce the tumor growth in HepG2-xenograft mice better than curcumin. CurDD also exerted the stronger inhibition on VEGF secretion, COX-2 and Bcl-2 expression and induced higher Bax expression in comparison with curcumin. The results suggest that CurDD is a promising prodrug of curcumin and has a potential to be further developed as a therapeutic agent or an adjuvant for the treatment of hepatocellular carcinoma.

Hepatocellular carcinomas are promoted by tocopheryl acetate but eliminated by tocopheryl succinate

BackgroundThe major causes of hepatocellular carcinomas are Aflatoxin, hepatitis B and hepatitis C viruses.Alpha tocopherol and its acetate and succinate esters have each been reported as counteracting cancer development in humans and rodents. We have investigated their salutary effect in both poor and high quality diets in rainbow trout Oncorhynchus mykiss as a model. MethodsHepatocellular carcinomas (HCCs) were induced in rainbow trout by dietary aflatoxin B1 (AfB1). A matrix of different levels of several vitamins and vitamin analogues were included in selected diets as possible anticancer agents. Identification of HCCs was made by histopathology. Results1.) Elevated dietary tocopheryl acetate (E-Ac) caused a marked increase in liver size and in AfB1-induced HCCs in rainbow trout. 2.) Poor diets increased the HCC incidence. 3.) Elevated dietary tocopheryl succinate (E-Su) nearly eliminated HCC development in fish fed complete diets. Tocopheryl succinate in poor diets reduced HCCs by 77% compared to tocopheryl acetate diets. 4.) Trans-retinoic acid also reduced HCC incidence. 5.) Vitamins A and D deficiency caused tumor increases but had no effect on liver size. 6.) The use of casein and dextrin in the place of soybean textured vegetable protein, in poor diets nearly eliminated the HCC risk. 7.) Trout sera showed all three vitamin forms; free α-tocopherol (E-OH), tocopheryl acetate (E-Ac) and tocopheryl succinate (E-Su), from diets containing any of these vitamin analogues, suggesting both de-esterification and trans-esterification. 8.) E-Su is discussed in the light of an anti-cancer agent that is non toxic to normal tissue but that cohorts to it are needed. ConclusionsIncreased dietary E-Ac escalated AfB1 induced HCCs and caused hepatomegaly in rainbow trout, while E-Su eliminated the HCC risk as shown by histopathology.

Carboxylesterase-2-Selective Two-Photon Ratiometric Probe Reveals Decreased Carboxylesterase-2 Activity in Breast Cancer Cells.

Human carboxylesterase-2 (CE2) is a carboxylesterase that catalyzes the hydrolysis of endogenous and exogenous substrates. Abnormal CE2 levels are associated with various cancers, and CE2 is a key mediator of anticancer prodrugs, including irinotecan. Here, we developed a two-photon ratiometric probe for detecting CE2 activity using succinate ester as a recognition site for CE2. The probe showed high selectivity to CE2, a clear emission color change, high photostability, and bright two-photon microscopy (TPM) imaging capability, allowing the quantitative detection of CE2 activity in live cells. Using TPM ratio analysis, we show for the first time that CE2 activity was much lower in breast cancer cells than in normal cells. In CE2 overexpression studies, cancer cells had a markedly enhanced sensitivity to the cytotoxic effect of irinotecan, corresponding well with the TPM ratio of the probe. These results may provide useful information for quantitatively measuring CE2 activity in situ and predicting the responsiveness to anticancer drugs.

Synthesis and Cerebrovascular Anti-Ischemic Activity of New 5-Hydroxyadamantan-2-One Derivatives

New 5-hydroxyadamantan-2-one derivatives with heteroaromatic, aromatic, and aliphatic acids (nicotinic, succinic, p-chlorophenoxyacetic, 3,4,5-trimethoxybenzoic, and anisic) were synthesized. Their pharmacological properties were studied to discover compounds with cerebrovascular anti-ischemic activity and without hypotensive activity. Esters of succinic acid and 5-hydroxyadamantan-2-one (diester Ia and monoester Ib, 100 mg/kg, i.v.) exhibited the most potent effect on cerebral circulation under ischemic conditions. They did not lower arterial blood pressure. The monoester was less toxic with LD50 740.0 (676.0 – 804.0) mg/kg. Analysis of the cerebrovascular effects of the succinate esters of 5-hydroxyadamantan-2-one using bicuculline revealed a GABA-ergic mechanism of action on cerebral vessels. However, radioligand analysis in vitro using the specific ligand [3H]-SR 95531 found that these esters did not compete for rat-brain membrane GABAA-receptors. Thus, the monoester of succinic acid and 5-hydroxyadamantan-2-one possessed pronounced cerebrovascular anti-ischemic activity and did not produce hypotensive effects. The latter circumstance differentiated it from well-known drugs used in neurology (picamilon, Mexidol, nimodipine, cinnarizine, and Cavinton).

Comparative study of RS4 type resistant starches derived from cassava and potato starches via octenyl succinylation

Resistant starch is becoming important among functional foods because of its similarity to dietary fiber in many physiological properties. In the present study, an attempt has been made to compare two distinct tuber starches from cassava and potato, in the formation of RS4 type resistant starch by chemical modification with octenyl succinic anhydride (OSA). The octenyl succinate esters of both the starches exhibited significant changes in structural, functional, and dietetic properties in comparison to their respective native counterparts. The modified starches were characterized by FTIR, SEM, and XRD analysis. The pasting, gelatinization, and in vitro digestibility properties were also determined. The water binding capacity of both the starches increased upon modification. The pasting and gelatinization properties of the two starches were affected differently. The cooked samples of octenyl succinylated potato starch showed slowly digestible starch (SDS) and resistant starch (RS) in the range of 10.53–34.86% and 3.58–29.1%, respectively, whereas these were 20.46–38.36% and 1.47–27.92%, respectively, for cassava starch. In both cases, RS and SDS of modified starches increased significantly and glycemic index (GI) decreased in comparison to corresponding native starches.

Succinate ester derivative of \u03b4-tocopherol enhances the protective effects against 60Co \u03b3-ray-induced hematopoietic injury through granulocyte colony-stimulating factor induction in mice

α-tocopherol succinate (α-TOS), γ-tocotrienol (GT3) and δ-tocotrienol (DT3) have drawn large attention due to their efficacy as radioprotective agents. α-TOS has been shown to act superior to α-tocopherol (α-TOH) in mice by reducing lethality following total body irradiation (TBI). Because α-TOS has been shown to act superior to α-tocopherol (α-TOH) in mice by reducing lethality following total body irradiation (TBI), we hypothesized succinate may be contribute to the radioprotection of α-TOS. To study the contributions of succinate and to identify stronger radioprotective agents, we synthesized α-, γ- and δ-TOS. Then, we evaluated their radioprotective effects and researched further mechanism of δ-TOS on hematological recovery post-irradiation. Our results demonstrated that the chemical group of succinate enhanced the effects of α-, γ- and δ-TOS upon radioprotection and granulocyte colony-stimulating factor (G-CSF) induction, and found δ-TOS a higher radioprotective efficacy at a lower dosage. We further found that treatment with δ-TOS ameliorated radiation-induced pancytopenia, augmenting cellular recovery in bone marrow and the colony forming ability of bone marrow cells in sublethal irradiated mice, thus promoting hematopoietic stem and progenitor cell recovery following irradiation exposure. δ-TOS appears to be an attractive radiation countermeasure without known toxicity, but further exploratory efficacy studies are still required.

A simple sample preparation for simultaneous determination of chloramphenicol and its succinate esters in food products using high-performance liquid chromatography/high-resolution mass spectrometry

ABSTRACTA simple method is described for the determination of chloramphenicol and its succinate esters in food products. Examination of food products using high-performance liquid chromatography/high-resolution mass spectrometry showed the presence not only of chloramphenicol but also of its succinate forms. A scheme is proposed for determining chloramphenicol and its succinate esters (calculated as chloramphenicol) in meat (beef, pork, poultry), milk, liver, kidney, eggs, fish and honey. Analytes are extracted from a 1.0 g sample with 5 ml acetonitrile. It was found that using the method of standard addition and diluting the extract with water leads to the elimination of matrix effects and also eliminates errors associated with peak splitting due to the separate elution of the differing forms of the analyte. Validation results were satisfactory, with recoveries from 85% to 111% (meat, milk, liver, kidney, eggs, fish and honey) and a relative standard deviation (RSD) lower than 13% for spiked levels of 0.3, 1.0 and 5 µg kg–1. The limits of detection and quantification (calculated as chloramphenicol for all forms) were 0.1 and 0.3 µg kg–1, respectively. The RSD of the results of the analysis was < 10%. The duration of the analysis was less than 1 h.

Cytotoxic naphthoquinone and a new succinate ester from the soil fungus Fusarium solani PSU-RSPG227

A new naphthoquinone, solaninaphthoquione (1), and a new succinate ester derivative, 4-(4-hydroxyphenethoxy)-4-oxobutanoic acid (2), were isolated from the soil fungus Fusarium solani PSU-RSPG227 together with five previously reported compounds; javanicin (3), monaspilosin (4), aspergillol B (5), tyrosol (6) and 4-hydroxyphenylacetic acid (7). Their structures were elucidated primarily by NMR spectroscopic data. Due to paucity of materials, compounds 2, 4 and 5 as well as analogues of 5 were prepared for biological activity evaluation. Compound 1 showed significant cytotoxic activity against breast cancer (MCF-7) cells and mild cytotoxic activity against oral human carcinoma (KB) cells (IC50 values of 21.3 and 22.6μM, respectively) compared to standard compounds. Compound 1 also displayed weak antimalarial activity (IC50 of 26.1μM).

Hyaluronic acid-quercetin conjugate micelles: Synthesis, characterization, in vitro and in vivo evaluation

A tumor cell-targeted prodrug was developed for quercetin, using hyaluronic acid as polymeric carrier. Hyaluronic acid-quercetin (HA-QT) bioconjugates were synthesized by linking the hydroxy of quercetin via a succinate ester to adipic dihydrazide-modified hyaluronic acid. The mirco-morphology demonstrated that the prepared prodrug could form self-assembled micelles possessing spherical shape, 172.1nm average diameter and −20.30mV surface potential. The HA-QT micelles exhibited significant sustained and pH-dependent drug release behaviors without dramatic initial burst. Compared to free quercetin solution, the HA-QT micelles were found a 4 times increase in cytotoxicity on MCF-7 cells (CD44-overexpressing cell lines), while weak enhancement in inhibitory activity was observed towards L929 cells (CD44 deficient cell lines). Promisingly, 20.1-fold increase in the half-life and 4.9-fold increase in the area-under-the-curve (AUC) of quercetin were achieved for the HA-QT micelles compared with the parent drug. In addition, the HA-QT micelles also showed excellent inhibition effect on tumor growth in H22 tumor-bearing mice. Hemolytic toxicity and vein irritation assay further suggested that the HA-QT micelles were a safe and potent drug delivery system for targeted antitumor therapy.

ROS-triggered and regenerating anticancer nanosystem: An effective strategy to subdue tumor's multidrug resistance

Drug delivery strategies utilizing tumor microenvironment are recognized as a critical doorway to overcome multidrug resistance (MDR). However, the variability of tumor microenvironment at different disease stages would definitely minimize stimuli generation and eventually the therapeutic effects of these stimuli sensitive systems. Herein, we report a unique reactive oxygen species (ROS) triggered nanosystem that can replenish the ROS upon disassembly to maintain its high level. This was accomplished by a new amphiphilic polymer (TBH) composed of D-α-tocopherol polyethylene glycol 1000 succinate (TPGS), hyaluronic acid (HA) and arylboronic ester. As a linker of TPGS to HA, arylboronic ester could efficiently degrade in response to ROS resulting in dismantling of nanosystem followed by rapid release of TPGS. Owing to ROS inducing activity of TPGS with mitochondrial respiratory complex II, ROS regeneration was observed for TBH nanosystem both in MCF-7/ADR cells and tumor tissues xenografted with MCF-7/ADR cells. Furthermore, doxorubicin-loaded TBH nanosystem (DOX-TBH) revealed higher drug cytotoxicity due to enhanced retention effect on account of ROS triggered DOX release and P-gp inhibitory mechanism of TPGS. Moreover, HA significantly improved tumor targeting capability of DOX-TBH, while ROS based triggering and regenerating mechanism lead to marked inhibition of the tumor growth in the xenograft MCF-7/ADR tumor-bearing nude mice.

Succinate esters: odd-even effects in melting points.

Dialkyl succinates show a pattern of alternating behavior in their melting points, as the number of C atoms in the alkane side chain increases, unlike in the dialkyl oxalates [Joseph et al. (2011). Acta Cryst. B67, 525-534]. Dialkyl succinates with odd numbers of C atoms in the alkyl side chain show higher melting points than the immediately adjacent analogues with even numbers. The crystal structures and their molecular packing have been analyzed for a series of dialkyl succinates with 1-4 C atoms in the alkyl side chain. The energy difference (ΔE) between the optimized and observed molecular conformations, density, Kitaigorodskii packing index (KPI) and C-H...O interactions are considered to rationalize this behavior. In contrast to the dialkyl oxalates where a larger number of moderately strong C-H...O interactions were characteristic of oxalates with elevated melting points, here the molecular packing and the density play a major role in raising the melting point. On moving from oxalate to succinate esters the introduction of the C2 spacer adds two activated H atoms to the asymmetric unit, resulting in the formation of stronger C-H...O hydrogen bonds in all succinates. As a result the crystallinity of long-chain alkyl substituted esters improves enormously in the presence of hydrogen bonds from activated donors.