Molecular docking studies, DFT, and ADMET calculations of some flavonoids and their characteristic structural features involved in inhibition of pro-inflammatory enzymes.

Inflammation is an immune system response triggered by pathogens, damaged cells, or stimuli. Some regulatory enzymes, such as phosphodiesterase, hyaluronidase, collagenase, and lipoxygenase, play an essential role in the inflammatory process. Polyphenolic compounds, such as flavonoids, are active suppressors of inflammatory cytokines, modulators of transcription factors, and inflammation-related pathways. A set of flavonoid structures was screened and docked against inflammation pathway enzymes. Amentoflavone has been shown to cause interactions with phosphodiesterase enzymes, while Bilobetin and Silibinin demonstrated an increase in binding energy with collagenase enzymes. The retrieved compounds from the docking study were subjected to DFT theory. The results showed that the LUMO orbital is located on the flavonoid part. The thermochemical parameters indicated that Silibinin is more stable than other compounds. The ADMET profile predicted that Silibinin can be used orally among the compounds. Silibinin can be introduced as a promising anti-inflammatory agent demonstrating phosphodiesterase and collagenase inhibitory properties.

Decrypting the molecular basis of cellular drug phenotypes by dose-resolved expression proteomics.

Proteomics is making important contributions to drug discovery, from target deconvolution to mechanism of action (MoA) elucidation and the identification of biomarkers of drug response. Here we introduce decryptE, a proteome-wide approach that measures the full dose-response characteristics of drug-induced protein expression changes that informs cellular drug MoA. Assaying 144 clinical drugs and research compounds against 8,000 proteins resulted in more than 1 million dose-response curves that can be interactively explored online in ProteomicsDB and a custom-built Shiny App. Analysis of the collective data provided molecular explanations for known phenotypic drug effects and uncovered new aspects of the MoA of human medicines. We found that histone deacetylase inhibitors potently and strongly down-regulated the T cell receptor complex resulting in impaired human T cell activation in vitro and ex vivo. This offers a rational explanation for the efficacy of histone deacetylase inhibitors in certain lymphomas and autoimmune diseases and explains their poor performance in treating solid tumors.

Decrypting lysine deacetylase inhibitor action and protein modifications by dose-resolved proteomics.

Lysine deacetylase inhibitors (KDACis) are approved drugs for cutaneous T cell lymphoma (CTCL), peripheral T cell lymphoma (PTCL), and multiple myeloma, but many aspects of their cellular mechanism of action (MoA) and substantial toxicity are not well understood. To shed more light on how KDACis elicit cellular responses, we systematically measured dose-dependent changes in acetylation, phosphorylation, and protein expression in response to 21 clinical and pre-clinical KDACis. The resulting 862,000 dose-response curves revealed, for instance, limited cellular specificity of histone deacetylase (HDAC) 1, 2, 3, and 6 inhibitors; strong cross-talk between acetylation and phosphorylation pathways; localization of most drug-responsive acetylation sites to intrinsically disordered regions (IDRs); an underappreciated role of acetylation in protein structure; and a shift in EP300 protein abundance between the cytoplasm and the nucleus. This comprehensive dataset serves as a resource for the investigation of the molecular mechanisms underlying KDACi action in cells and can be interactively explored online in ProteomicsDB.

A combination of virtual screening, molecular dynamics simulation, MM/PBSA, ADMET, and DFT calculations to identify a potential DPP4 inhibitor.

DPP4 inhibitors can control glucose homeostasis by increasing the level of GLP-1 incretins hormone due to dipeptidase mimicking. Despite the potent effects of DPP4 inhibitors, these compounds cause unwanted toxicity attributable to their effect on other enzymes. As a result, it seems essential to find novel and DPP4 selective compounds. In this study, we introduce a potent and selective DPP4 inhibitor via structure-based virtual screening, molecular docking, molecular dynamics simulation, MM/PBSA calculations, DFT analysis, and ADMET profile. The screened compounds based on similarity with FDA-approved DPP4 inhibitors were docked towards the DPP4 enzyme. The compound with the highest docking score, ZINC000003015356, was selected. For further considerations, molecular docking studies were performed on selected ligands and FDA-approved drugs for DPP8 and DPP9 enzymes. Molecular dynamics simulation was run during 200 ns and the analysis of RMSD, RMSF, Rg, PCA, and hydrogen bonding were performed. The MD outputs showed stability of the ligand-protein complex compared to available drugs in the market. The total free binding energy obtained for the proposed DPP4 inhibitor was more negative than its co-crystal ligand (N7F). ZINC000003015356 confirmed the role of the five Lipinski rule and also, have low toxicity parameter according to properties. Finally, DFT calculations indicated that this compound is sufficiently soft.

Illuminating phenotypic drug responses of sarcoma cells to kinase inhibitors by phosphoproteomics.

Kinase inhibitors (KIs) are important cancer drugs but often feature polypharmacology that is molecularly not understood. This disconnect is particularly apparent in cancer entities such as sarcomas for which the oncogenic drivers are often not clear. To investigate more systematically how the cellular proteotypes of sarcoma cells shape their response to molecularly targeted drugs, we profiled the proteomes and phosphoproteomes of 17 sarcoma cell lines and screened the same against 150 cancer drugs. The resulting 2550 phenotypic profiles revealed distinct drug responses and the cellular activity landscapes derived from deep (phospho)proteomes (9-10,000 proteins and 10-27,000 phosphorylation sites per cell line) enabled several lines of analysis. For instance, connecting the (phospho)proteomic data with drug responses revealed known and novel mechanisms of action (MoAs) of KIs and identified markers of drug sensitivity or resistance. All data is publicly accessible via an interactive web application that enables exploration of this rich molecular resource for a better understanding of active signalling pathways in sarcoma cells, identifying treatment response predictors and revealing novel MoA of clinical KIs.

Design, synthesis and evaluation of novel 1,2,4-triazole derivatives as promising anticancer agents.

Herein, we reported the synthesis of nineteen novel 1,2,4-triazole derivatives including 1,3-diphenyl-2-(1H-1,2,4-triazol-1-yl) propan-1-ones (7a-e), 1-(1,3-diphenylpropan-2-yl)-1H-1,2,4-triazole (8a-c) and 1,4-diphenyl-2-(1H-1,2,4-triazol-1-yl) butane-1,4-diones (10a-k). The structures of these derivatives were confirmed by spectroscopic techniques like IR, 1H-NMR, Mass spectroscopy and Elemental analysis. The cytotoxic activities of the synthesized compounds were evaluated against three human cancer cell lines including MCF-7, Hela and A549 using MTT assay. Compounds 7d, 7e, 10a and 10d showed a promising cytotoxic activity lower than 12 µM against Hela cell line. The safety of these compounds was also, evaluated on MRC-5 as a normal cell line and relieved that most of the synthesized compounds have proper selectivity against normal and cytotoxic cancerous cell lines. Finally, molecular docking studies were also, done to understand the mechanism and binding modes of these derivatives in the binding pocket of aromatase enzyme as a possible target.

Phytochemical Analysis and Biological Activity of Salvia compressa Vent.

Background: Salvia extracts have various biological activities and are rich sources of bioactive metabolites. Objectives: We identified five phytochemicals from S. compressa extract and assessed its biological properties. Methods: The plant's shoots were extracted using dichloromethane, and the constituents were isolated using column chromatography. High-resolution NMR spectroscopy characterized the chemical structures of the compounds (1 - 5). The cytotoxic effect of the extract was examined against MCF-7 cells by MTT reduction assay, while cisplatin was tested as a reference cytotoxic compound. The antibacterial activity was assessed using nutrient broth micro-dilution (NBMD), and chloramphenicol was used as the positive control. Results: Citrostadienol (1), ß-sitosterol (2), two glyceride esters of linolenic, linoleic, and palmitic acids (3, 4), and geraniol (5) were isolated from S. compressa for the first time. The extract showed activity against MCF-7 breast cancer cells and reduced cell viability to 68.2 ± 13.1% compared to the control drug at the concentration of 50 µg/mL, while it was not active against seven test bacteria. Conclusions: The anti-complementary activity of the isolated steroids suggests S. compressa for future anti-inflammatory research.

A highly potential cleavable linker for tumor targeting antibody-chemokines.

Chemokines are the large family of chemotactic cytokines that play an important role in leukocyte movement and migration stimulation. Until now, several antibody-cytokine (chemokine) fusion proteins have been investigated in clinical trials because of their ability to evoke the circulating leukocytes far from the tumor site. In this case, creating the concentration gradient regarding the chemokine is very important to recruit the circulating leukocytes with maximum performance to the tumor environment. To achieve a proper gradient, the chemokine separation from the tumor antigen-bounded antibody can be very crucial. Thus, we designed a novel linker that can be cleaved by enzymes presented around the tumor site including cathepsin B, urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs). Also, it can inhibit tumor progression by competing with the native substrate of key proteases in the tumor microenvironment. The proposed linker was evaluated using some bioinformatics approaches. In silico results showed that the linker is structurally stable and could be detected and cleaved using the mentioned enzymes.Communicated by Ramaswamy H. Sarma.

Synthesis, cytotoxicity assay, pharmacokinetics, biodistribution and modeling study of cabazitaxel-dextran nanoconjugates: targeted vs non targeted delivery.

Cabazitaxel (CTX) is an anti-neoplastic agent of second-generation taxane derivatives, characterized by very low water solubility. The currently marketed formulation of CTX contains high concentrations of surfactant and ethanol, which causes severe hypersensitivity reactions in patients. To deal with aforementioned side effects, our previous study attempted to develop the prodrugs of CTX with dextran. Here our approach differs through synthesizing folate containing prodrug and also investigating cytotoxicity and pharmacokinetics parameters obtained with dextran and dextran-folate nanoconjugates versus free CTX. MCF-7 with medium folate receptor expression and MDA-MB-231 as high folate receptor expression cell lines were selected for cytotoxicity assay. Pharmacokinetics properties were studied by injecting prodrugs and CTX to Wistar rats, analyzing serum and selected tissue samples and the obtained results were sibjected to data modeling study. The size of synthesized prodrugs was mostly less than 90 nm. Folate conjugates provided higher toxicity in comparison with dextran conjugates on both cell lines. In vivo non-compartmental pharmacokinetics analysis revealed enhanced area under the curve (about 3-5 fold for different samples) and longer half-life (approximately 1.3-1.8 fold higher) which led to increased serum residence time of prodrugs in comparison to free CTX. Tissue accumulation data showed that liver was the major organ with high accumulation of CTX. The accumulation of folate conjugates was remarkably higher than dextran samples (p < 0.05 in samples of 2, 10 and 24 h). Data modeling by Principal Component Analysis (PCA) and Hierarchical Cluster models showed a significant difference between pharmacokinetics properties of CTX and prodrugs. In summary, prodrugs seem to be proper and promising CTX delivery systems as substitution for the current market formulation.

Design, synthesis, and biological evaluation of symmetrical azine derivatives as novel tyrosinase inhibitors.

A series of symmetrical azine derivatives containing different substituted benzyl moieties were designed, synthesized, and evaluated for their inhibitory activity against tyrosinase. The results showed that compounds 3e, 3f, 3h, 3i, 3j, and 3k possess effective tyrosinase inhibition with IC50 values ranging from 7.30 µM to 62.60 µM. Particularly, compounds 3f displayed around three-fold improvement in the potency (IC50 = 7.30 ± 1.15 µM) compared to that of kojic acid (IC50 = 20.24 ± 2.28 µM) as the positive control. Kinetic study of compound 3f confirmed uncompetitive inhibitory activity towards tyrosinase indicating that it can bind to enzyme-substrate complex. Next, molecular docking analysis was performed to study the interactions and binding mode of the most potent compound 3f in the tyrosinase active site. Besides, the cytotoxicity of 3f, as well as its potency to reduce the melanin content were also measured on invasive melanoma B16F10 cell line. Also, 3f exhibited above 82% cell viability in the A375 cell line at 10 µM. Consequently, compounds 3f could be introduced as a potent tyrosinase inhibitor that might be a promising candidate in the cosmetics, medicine, and food industry.

Exploring pH dependent delivery of 5-fluorouracil from functionalized multi-walled carbon nanotubes.

Multi-walled carbon nanotubes (MWCNTs) can be applied for pH-sensitive delivery of anticancer drugs. Due to the importance of 5-fluorouracil (5-FU) in different tumor therapy regimens, it has been widely used in different pH dependent drug delivery systems. To investigate the pH effects on loading (and release) of 5-FU on (and from) the functionalized MWCNTs and propose the optimum condition for drug delivery, both macroscopic and microscopic studies were carried out using chromatography and molecular dynamic simulation at different conditions. For both levels of studies, different analytical approaches were performed to assess the validity of the methods. The experimental results revealed that 5-FU has more binding affinity to the surface of the nanocarrier at physiological pH (pH = 7.4) and showed more release at acidic conditions (pH = 5.0). Meanwhile it has been observed that basic pH (pH = 9.0) can lead to a dramatic decrease effect on loading of the drug. The results of this study can be used to suggest the optimum pH levels for nanocarbon based formulations of 5-FU in cancer therapy.

A systems pharmacology approach to identify the autophagy-inducing effects of Traditional Persian medicinal plants.

Aging is correlated with several complex diseases, including type 2 diabetes, neurodegeneration diseases, and cancer. Identifying the nature of this correlation and treatment of age-related diseases has been a major subject of both modern and traditional medicine. Traditional Persian Medicine (TPM) embodies many prescriptions for the treatment of ARDs. Given that autophagy plays a critical role in antiaging processes, the present study aimed to examine whether the documented effect of plants used in TPM might be relevant to the induction of autophagy? To this end, the TPM-based medicinal herbs used in the treatment of the ARDs were identified from modern and traditional references. The known phytochemicals of these plants were then examined against literature for evidence of having autophagy inducing effects. As a result, several plants were identified to have multiple active ingredients, which indeed regulate the autophagy or its upstream pathways. In addition, gene set enrichment analysis of the identified targets confirmed the collective contribution of the identified targets in autophagy regulating processes. Also, the protein-protein interaction (PPI) network of the targets was reconstructed. Network centrality analysis of the PPI network identified mTOR as the key network hub. Given the well-documented role of mTOR in inhibiting autophagy, our results hence support the hypothesis that the antiaging mechanism of TPM-based medicines might involve autophagy induction. Chemoinformatics study of the phytochemicals using docking and molecular dynamics simulation identified, among other compounds, the cyclo-trijuglone of Juglans regia L. as a potential ATP-competitive inhibitor of mTOR. Our results hence, provide a basis for the study of TPM-based prescriptions using modern tools in the quest for developing synergistic therapies for ARDs.

An Assay on the Possible Effect of Essential Oil Constituents on Receptors Involved in Women's Hormonal Health and Reproductive System Diseases.

Aromatic herbal remedies, hydrosols, and essential oils are widely used for women's hormonal health. Scientific investigation of their major constituents may prevent unwanted infertility cases, fetal abnormalities, and drug-herb interactions. It also may lead to development of new medications. A list of 265 volatile molecules (mainly monoterpenes and sesquiterpenes) were prepared from a literature survey in Scopus and PubMed (2000-2019) on hydrosols and essential oils that are used for women's hormonal and reproductive health conditions. The PDB (protein data bank) files of the receptors (136 native PDB files) that involve with oxytocin, progesterone, estrogen, prolactin, acetyl choline, androgen, dopamine, human chorionic gonadotropin, luteinizing hormone, follicle-stimulating hormone, aromatase, and HER2 receptors were downloaded from Protein Data Bank. An in silico study using AutoDock 4.2 and Vina in parallel mode was performed to investigate possible interactions of the ligands with the receptors. Drug likeliness was investigated for the most active molecules using DruLiTo software. Aristola-1(10),8-diene, bergapten (5-methoxypsoralen), α-bergamotene, bicyclogermacrene, α-bisabolol oxide A, α-bisabolone oxide, p-cymen-8-ol, 10-epi elemol, α-elemol, ß-eudesmol, 7-epi-ß-eudesmol, ficusin, ß-humulene, methyl jasmonate, nerolidol, pinocarvone, (+)-spathulenol, and thujone had better interactions with some androgen, aromatase, estrogen, progesterone, HER2, AChR, and/or dopamine receptors. Most of these molecules had an acceptable drug likeliness except for α-bergamotene, bicyclogermacrene, ß-humulene, and aristola-1(10),8-diene. Some volatile natural molecules can be considered as lead compound for drug development to treat hormonal conditions.

Partial least Squares- least squares- Support Vector Machine Modeling of ATR-IR as a Spectrophotometric Method for Detection and Determination of Iron in Pharmaceutical Formulations.

Iron is an essential element used as supplement in different dosage-forms. Different time and expenditure-consuming methods introduced for detection and determination of elemental ions such as Atomic Absorption Spectroscopy. In this research, two different and routine methods containing ATR-IR and atomic absorption were applied to define the amount of iron in 198 samples containing different concentrations of commercial iron drops and syrups and the output data of the methods was transferred to chemometric model to compare the accuracy and robustness of the methods. By applying this mathematical model, in addition to the confirmation of ATR-IR (a time and energy-saving method) as a replacement of Atomic Absorption Spectroscopy to produce the same results, chemometrical model was used to evaluate the output data in a faster and easier method. At first, ATR-IR spectra data converted to normal matrix by SNV preprocessing approach. Then, a relationship between iron concentrations achieved by AAS and ATR-IR data was established using PLS-LS-SVM. Consequently, model was able to predict ~99% of the samples with low error-values (root mean square-error of cross-validation equal to 0.98). Y-permutation test performed to confirm that the model was not assessed accidentally. Although, chemometric methods for detection of some heavy metals have been reported in the literature, combination of PLS-LS-SVM with ATR-IR was not cited. In this study a fast and robust method for iron assay was suggested.As a result, ATR-IR can be a suitable method in detection and qualification of iron-content in pharmaceutical dosage forms with less energy-consumption but similar accuracy.

Application of molecular dynamics simulations to design a dual-purpose oligopeptide linker sequence for fusion proteins.

Proteins are often monitored by combining a fluorescent polypeptide tag with the target protein. However, due to the high molecular weight and immunogenicity of such tags, they are not suitable choices for combining with fusion proteins such as immunotoxins. In this study, we designed a polypeptide sequence with a dual role (it acts as both a linker and a fluorescent probe) to use with fusion proteins. Two common fluorescent tag sequences based on tetracysteine were compared to a commonly used rigid linker as well as our proposed dual-purpose sequence. Computational investigations showed that the dual-purpose sequence was structurally stable and may be a good choice to use as both a linker and a fluorescence marker between two moieties in a fusion protein.

Evaluation of the effect of topical chamomile (Matricaria chamomilla L.) oleogel as pain relief in migraine without aura: a randomized, double-blind, placebo-controlled, crossover study.

Phytotherapy is a source of finding new remedies for migraine. Traditional chamomile oil (chamomile extraction in sesame oil) is a formulation in Persian medicine (PM) for pain relief in migraine. An oleogel preparation of reformulated traditional chamomile oil was prepared and then standardized based on chamazulene (as a marker in essential oil) and apigenin via gas chromatography (GC) and high-performance liquid chromatography (HPLC) methods, respectively. A crossover double-blind clinical trial was performed with 100 patients. Each patient took two tubes of drug and two tubes of placebo during the study. Visual analog scale (VAS) questionnaires were filled in by the patients and scores were given, ranging from 0 to 10 (based on the severity of pain) during 24 h. Other complications like nausea, vomiting, photophobia, and phonophobia were also monitored. There was 4.48 ± 0.01 µl/ml of chamazulene and 0.233 mg/g of apigenin in the preparation (by correcting the amount with extraction ratio). Thirty-eight patients in the drug-placebo and 34 patients in the placebo-drug groups (a total number of 72 patients as per protocol) completed the process in the randomized controlled trial (RCT). Adapted results from the questionnaires showed that pain, nausea, vomiting, photophobia, and phonophobia significantly (p < 0.001) decreased by using chamomile oleogel on the patients after 30 min. Results supported the efficacy of chamomile oleogel as a pain relief in migraine without aura.

Synthesis and characterization of some novel diaryl urea derivatives bearing quinoxalindione moiety.

Diaryl urea derivatives have exhibited a broad spectrum of biochemical effects and pharmaceutical applications. Several diaryl urea derivatives such as sorafenib, regorafenib, linifanib, and tivozanib and lenvatinib are in clinical trial or clinical use. Therefore, development of small molecules within the diaryl urea scaffold with the ability of binding to variety of enzymes and receptors in the biological system are an interesting topic for researchers. Sorafenib as a diaryl urea derivative is a well-known anticancer agent. Corresponding to available information about biological activities of quinoxaline moieties, based on sorafenib scaffold, several structures were designed by replacement of pyridyl carboxamide group of sorafenib with quinoxalindione moiety. A total of 14 novel compounds in 7 synthetic steps were synthesized. Briefly, the amino group of p-aminophenol was first protected followed by O-arylation of 4-acetamidophenol with 5-chloro-2-nitroaniline to provide 5-(4-acetamidophenoxy)-2-nitroaniline. Reduction of the nitro group of 5-(4-acetamidophenoxy)-2-nitroaniline and cyclization of diamine N-(4-(3,4-diaminophenoxy) phenyl) acetamides with oxalic acid afforded compound N-(4-((2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy)phenyl) acetamides which on deacetylation gave compounds 6-(4-aminophenoxy) quinoxaline-2,3 (1H, 4H)-diones. Then resultant compounds, 6-(4-aminophenoxy) quinoxaline-2,3 (1H, 4H)-diones were reacted by appropriate isocyanates/ carbamates to give the target compounds 1-(4-((2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy)phenyl)-3-phenylureas. The structures of compounds confirmed by proton nuclear magnetic resonance (1H NMR), mass spectrum and Fourier transform infrared (FT-IR).

Biological evaluation, docking and molecular dynamic simulation of some novel diaryl urea derivatives bearing quinoxalindione moiety.

In this study a series of diarylurea derivatives containing quinoxalindione group were biologically evaluated for their cytotoxic activities using MTT assay against MCF-7 and HepG2 cell lines. Antibacterial activities of these compounds were also evaluated by Microplate Alamar Blue Assay (MABA) against three Gram-negative (Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi), three Gram-positive (Staphylococcus aureus, Bacillus subtilis and Listeria monocitogenes) and one yeast-like fungus (Candida albicans) strain. Furthermore, molecular docking was carried out to study the binding pattern of the compounds to the active site of B-RAF kinase (PDB code: 1UWH). Molecular dynamics simulation was performed on the best ligand (16e) to investigate the ligand binding dynamics in the physiological environment. Cytotoxic evaluation revealed the most prominent cytotoxicity for 6 compounds with IC50 values of 10-18 µM against two mentioned cell lines. None of the synthesized compounds showed significant antimicrobial activity. The obtained results of the molecular docking study showed that all compounds fitted in the binding site of enzyme with binding energy range of -11.22 to -12.69 kcal/mol vs sorafenib binding energy -11.74 kcal/mol as the lead compound. Molecular dynamic simulation indicated that the binding of ligand (16e) was stable in the active site of B-RAF during the simulation.

Reformulation of Traditional Chamomile Oil: Quality Controls and Fingerprint Presentation Based on Cluster Analysis of Attenuated Total Reflectance-Infrared Spectral Data.

Herbal oils have been widely used in Iran as medicinal compounds dating back to thousands of years in Iran. Chamomile oil is widely used as an example of traditional oil. We remade chamomile oils and tried to modify it with current knowledge and facilities. Six types of oil (traditional and modified) were prepared. Microbial limit tests and physicochemical tests were performed on them. Also, principal component analysis, hierarchical cluster analysis, and partial least squares discriminant analysis were done on the spectral data of attenuated total reflectance-infrared in order to obtain insight based on classification pattern of the samples. The results show that we can use modified versions of the chamomile oils (modified Clevenger-type apparatus method and microwave method) with the same content of traditional ones and with less microbial contaminations and better physicochemical properties.

Synthesis and Characterization of Water-soluble Conjugates of Cabazitaxel Hemiesters-Dextran.

BACKGROUND: Cabazitaxel (CTX) is a second- generation taxane derivative, a class of potent anticancer drugs with very low water solubility. CTX is used in patients with resistant prostate cancer unresponsive to the first generation taxane, docetaxel. Currently marketed formulations of CTX contain high concentrations of surfactant and ethanol, which cause severe hypersensitivity reactions in patients. METHODS: In order to increase its solubility, two hemiester analogs; CTX-succinate and CTX-glutarate were synthesized and characterized. To improve the solubility of hemiesters even more, dextran as a biocompatible polymer was also conjugated to hemiester analogs. MTT assay was performed on MCF-7 cell line to evaluate the cytotoxicity effect of hemiesters and conjugates. RESULTS: Based on the results, hemiester analogs increased water solubility of the drug up to about 3 and 8 fold. Conjugation to dextran enhanced the CTX solubility to more than 1500 fold. These conjugates released the conjugated CTX in less than 24 hours in a pH dependent manner and showed proper hemocompatibility characteristics. The hemiesters had approximately similar cytotoxicity in comparison with CTX and the dextran conjugates showed higher cytotoxicity effect on MCF-7 cell line.