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New amide conjugates of hydroxycinnamic acids (HCAs) and the known antineoplastic 5,11-dimethyl-5 H -indolo[2,3- b ]quinoline (DiMIQ), an analog of the natural alkaloid neocryptolepine, were synthesized and tested in vitro for anticancer activity. The compound 9-[((2-hydroxy)cinnamoyl)amino]-5,11-dimethyl-5 H -indolo[2,3- b ]quinoline ( 2 ), which contains the ortho-coumaric acid fragment, demonstrated dose-dependent effectiveness against both normal BxPC-3 and metastatic AsPC-1 pancreatic cancer cells. The IC 50 values for AsPC-1 and BxPC-3 were 336.5 nM and 347.5 nM, respectively, with a selectivity index of approximately 5 for both pancreatic cancer cells compared to normal dermal fibroblasts. Conjugate 2 did not exhibit any hemolytic activity against human erythrocytes at the tested concentration. Computational studies were performed to predict the pharmacokinetic profile and potential mechanism of action of the synthesized conjugates. These studies focused on the ADME properties of the conjugates and their interactions with DNA, as well as DNA-topoisomerase alpha and beta complexes. All of the conjugates studied showed approximately one order of magnitude stronger binding to DNA compared to the reference DiMIQ, and approximately two orders of magnitude stronger binding to the topoisomerase II-DNA complex compared to DiMIQ. Conjugate 2 was predicted to have the strongest binding to the enzyme-DNA complex, with a Ki value of 2.8 nM.

New protocol for the preparation of the novel caffeic acid derivatives using the Wittig reaction has been applied to follow the principles of green chemistry. The compounds have been evaluated against chloroquine-sensitive and chloroquine-resistant P. falciparum strains. Their cytotoxicity to normal human dermal fibroblasts and their propensity to induce hemolysis have been also determined. Ethyl (2 E )-3-(2,3,4-trihydroxyphenyl)-2-methylpropenoate has exhibited the highest antiplasmodial activity against P. falciparum strains without the cytotoxic and hemolytic effects. This derivative is significantly more potent than caffeic acid parent structure. The application of our one-step procedure has been shown to be rapid and efficient. It allows for an easy increase of input data to refine the structure-activity relationship model of caffeates as the antimalarials. The one-step approach meets the conditions of "atom economy" and eliminates hazardous materials. Water has been used as the effective medium for the Wittig reaction to avoid toxic organic solvents., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Katarzyna Sidoryk et al.)

Plant phenolic compounds have shown the ability to cooperate with one another at low doses in producing enhanced anticancer effects. This may overcome the limitations (e.g., poor bioavailability and high-dose toxicity) in developing these agents as cancer medicines. We have previously reported that the hydroxycinnamic acid derivative (HCAD) methyl-4-hydroxycinnamate and the phenolic diterpene carnosic acid (CA) can synergistically induce massive calcium-dependent apoptosis in acute myeloid leukemia (AML) at non-cytotoxic concentrations of each agent. Here, we explored the chemical nature of the synergy between HCADs and either CA, in inducing cytotoxicity, or the active metabolite of vitamin D (calcitriol), in enhancing the differentiation of AML cells. This was done by determining the structure-activity relationship of a series of hydroxycinnamic acids and their derivatives (methyl hydroxycinnamates and hydroxybenzylideneacetones) in combination with CA or calcitriol. The HCAD/CA synergy required the following critical structural elements of an HCAD molecule: (a) the para-hydroxyl on the phenolic ring, (b) the carbon C7-C8 double bond, and (c) the methyl-esterified carboxyl. Thus, the only HCADs capable of synergizing with CA were found to be methyl-4-hydroxycinnamate and methyl ferulate, which also most potently enhanced calcitriol-induced cell differentiation. Notably, the C7-C8 double bond was the major requirement for this HCAD/calcitriol cooperation. Our findings may contribute to the rational design of novel synergistically acting AML drugs based on prototype combinations of HCADs with other agents studied here.

Pharmacological and nutraceutical effects of isoflavones, which include genistein (GE), are attributed to their antioxidant activity protecting cells against carcinogenesis. The knowledge of the oxidation mechanisms of an active substance is crucial to determine its pharmacological properties. The aim of the present work was to explain complex oxidation processes that have been simulated during voltammetric experiments for our new thiolated genistein analog (TGE) that formed the self-assembled monolayer (SAM) on the gold electrode. The thiol linker assured a strong interaction of sulfur nucleophiles with the gold surface. The research comprised of the study of TGE oxidative properties, IR-ATR, and MALDI-TOF measurements of SAM before and after electrochemical oxidation. TGE has been shown to be electrochemically active. It undergoes one irreversible oxidation reaction and one quasi-reversible oxidation reaction in PBS buffer at pH 7.4. The oxidation of TGE results in electroactive products composed likely from TGE conjugates (e.g., trimers) as part of polymer. The electroactive centers of TGE and its oxidation mechanism were discussed using IR supported by quantum chemical and molecular mechanics calculations. Preliminary in-vitro studies indicate that TGE exhibits higher cytotoxic activity towards DU145 human prostate cancer cells and is safer for normal prostate epithelial cells (PNT2) than genistein itself.

Vitamins K exert a range of activities that extend far beyond coagulation and include anti-inflammatory effects, but the mechanisms involved in anti-inflammatory action remain unclear. In the present study, we showed that various forms of exogenous vitamins-K 1 , K 3 , K 2 (MK-4, MK-5, MK-6 and MK-7)-regulated a wide scope of inflammatory pathways in murine macrophages in vitro, including NOS-2, COX-2, cytokines and MMPs. Moreover, we demonstrated for the first time that macrophages are able to synthesise endogenous MK-4 on their own. Vitamins with shorter isoprenoid chains-K 1 , K 3 and MK-5-exhibited stronger anti-inflammatory potential than vitamins with longer isoprenoid chains (MK-6 and MK-7) and simultaneously were preferably used as a substrate for MK-4 endogenous production. Most interesting, atorvastatin pretreatment inhibited endogenous MK-4 production but had no impact on the anti-inflammatory activity of vitamins K. In summary, our results demonstrate that macrophages are able to synthesise endogenous MK-4 using exogenous vitamins K, and statin inhibits this process. However, the anti-inflammatory effect of exogenous vitamins K was independent of endogenous MK-4 synthesis.

Candida albicans forms extremely drug-resistant biofilms, which present a serious threat to public health globally. Biofilm-based infections are difficult to treat due to the lack of efficient antifungal therapeutics, resulting in an urgent demand for the development of novel antibiofilm strategies. In this study, the antibiofilm activity of DiMIQ (5,11-dimethyl-5 H -indolo[2,3- b ]quinoline) was evaluated against C. albicans biofilms. DiMIQ is a synthetic derivative of indoquinoline alkaloid neocryptolepine isolated from a medicinal African plant, Cryptolepis sanguinolenta . Antifungal activity of DiMIQ was determined using the XTT assay, followed by cell wall and extracellular matrix profiling and cellular proteomes. Here, we demonstrated that DiMIQ inhibited C. albicans biofilm formation and altered fungal cell walls and the extracellular matrix. Cellular proteomics revealed inhibitory action against numerous translation-involved ribosomal proteins, enzymes involved in general energy producing processes and select amino acid metabolic pathways including alanine, aspartate, glutamate, valine, leucine and isoleucine. DiMIQ also stimulated pathways of cellular oxidation, metabolism of carbohydrates, amino acids (glycine, serine, threonine, arginine, phenylalanine, tyrosine, tryptophan) and nucleic acids (aminoacyl-tRNA biosynthesis, RNA transport, nucleotide metabolism). Our findings suggest that DiMIQ inhibits C. albicans biofilms by arresting translation and multidirectional pathway reshaping of cellular metabolism. Overall, this agent may provide a potent alternative to treating biofilm-associated Candida infections.

Pancreatic cancer belongs to the most aggressive group of cancers, with very poor prognosis. Therefore, there is an important need to find more potent drugs that could deliver an improved therapeutic approach. In the current study we searched for selective and effective caffeic acid derivatives. For this purpose, we analyzed twelve compounds and evaluated their in vitro cytotoxic activity against two human pancreatic cancer cell lines, along with a control, normal fibroblast cell line, by the classic MTT assay. Six out of twelve tested caffeic acid derivatives showed a desirable effect. To improve the therapeutic efficacy of such active compounds, we developed a formulation where caffeic acid derivative (7) was encapsulated into liposomes composed of soybean phosphatidylcholine and DSPE-PEG 2000 . Subsequently, we analyzed the properties of this formulation in terms of basic physical parameters (such as size, zeta potential, stability at 4 °C and morphology), hemolytic and cytotoxic activity and cellular uptake. Overall, the liposomal formulation was found to be stable, non-hemolytic and had activity against pancreatic cancer cells (IC 50 19.44 µM and 24.3 µM, towards AsPC1 and BxPC3 cells, respectively) with less toxicity against normal fibroblasts. This could represent a promising alternative to currently available treatment options., Competing Interests: The authors declare no conflict of interest.

An efficient method of thiol group introduction to the structure of common natural products and synthetic active compounds with recognized biological efficacy such genistein ( 1 ), 5,11-dimethyl-5 H -indolo[2,3-b]quinolin ( 2 ), capecitabine ( 3 ), diosgenin ( 4 ), tigogenin ( 5 ), flumethasone ( 6 ), fluticasone propionate ( 7 ), ursolic acid methyl ester ( 8 ), and β-sitosterol ( 9 ) was developed. In most cases, the desired compounds were obtained easily via two-step processes involving esterification reaction employing S-trityl protected thioacetic acid and the corresponding hydoxy-derivative, followed by removal of the trityl-protecting group to obtain the final compounds. The results of our preliminary experiments forced us to change the strategy in the case of genistein ( 1 ), and the derivatization of diosgenin ( 4 ), tigogenin ( 5 ), and capecitabine ( 3 ) resulted in obtaining different compounds from those designed. Nevertheless, in all above cases we were able to obtain thiol-containing derivatives of selected biological active compounds. Moreover, a modelling study for the two-step thiolation of genistein and some of its derivatives was accomplished using the density functional theory (B3LP). A hypothesis on a possible reason for the unsuccessful deprotection of the thiolated genistein is also presented based on the semiempirical (PM7) calculations. The developed methodology gives access to new sulphur derivatives, which might find a potential therapeutic benefit.

Cancer is one of the leading causes of morbidity and mortality worldwide and nanotechnology has a significant potential to enhance the therapeutic and diagnostic performance of anti-cancer agents. Our work offers a simple and feasible strategy for thiocompound nanomedicines to be used in cancer therapy. Novel gold nanoparticles conjugated with thioabiraterone (AuNP-S-AB) were synthesized and significant new analytical methodologies were developed for their characterization by UV-Vis, TEM, IR, NMR and TGA. Our synthetic approach was based on the ligand exchange of citrates to thioabiraterone on gold nanoparticles. The average particle size of AuNP-S-AB was 14.5 nm with a spherical shape. The identity of thioabiraterone on the gold nanoparticles was proved by NMR and IR spectroscopy. The coverage of the gold nanoparticles with 40.9% (m/m) thioabiraterone was calculated from a TGA analysis. Molecular interactions between the thiol group of thioabiraterone and gold nanoparticles were evaluated through a combined experimental and theoretical study using the density functional theory (DFT). Additionally, an experiment conducted on hepatocytes or human prostate epithelial cells proved that newly synthesized thiol forms of abiraterone, as well as AuNP-S-AB, are more biocompatible than abiraterone. Our proposed idea of delivering abiraterone with our newly designed AuNP-S-AB may constitute a promising and novel prospect in cancer therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The assessment of both left (LV) and right ventricular (RV) motion is important to understand the impact of heart disease on cardiac function. The MRI technique of tissue phase mapping (TPM) allows for the quantification of regional biventricular three-directional myocardial velocities. The goal of this study was to establish normal LV and RV velocity parameters across a wide range of pediatric to adult ages and to investigate the feasibility of TPM for detecting impaired regional biventricular function in patients with repaired tetralogy of Fallot (TOF). Thirty-six healthy controls (age = 1-75 years) and 12 TOF patients (age = 5-23 years) underwent cardiac MRI including TPM in short-axis locations (base, mid, apex). For ten adults, a second TPM scan was used to assess test-retest reproducibility. Data analysis included the calculation of biventricular radial, circumferential, and long-axis velocity components, quantification of systolic and diastolic peak velocities in an extended 16 + 10 LV + RV segment model, and assessment of inter-ventricular dyssynchrony. Biventricular velocities showed good test-retest reproducibility (mean bias ≤ 0.23 cm/s). Diastolic radial and long-axis peak velocities for LV and RV were significantly reduced in adults compared to children (19-61%, p < 0.001-0.02). In TOF patients, TPM identified significantly reduced systolic and diastolic LV and RV long-axis peak velocities (20-50%, p < 0.001-0.05) compared to age-matched controls. In conclusion, tissue phase mapping enables comprehensive analysis of global and regional biventricular myocardial motion. Changes in myocardial velocities associated with age underline the importance of age-matched controls. This pilot study in TOF patients shows the feasibility to detect regionally abnormal LV and RV motion.

Acute myeloid leukemia (AML) is a malignant hematopoietic disease with poor prognosis for most patients. Conventional chemotherapy has been the standard treatment approach for AML in the past 40 years with limited success. Although, several targeted drugs were recently approved, their long-term impact on survival of patients with AML is yet to be determined. Thus, it is still necessary to develop alternative therapeutic approaches for this disease. We have previously shown a marked synergistic anti-leukemic effect of two polyphenols, curcumin (CUR) and carnosic acid (CA), on AML cells in-vitro and in-vivo . In this study, we identified another phenolic compound, methyl 4-hydroxycinnamate (MHC), which among several tested phytochemicals could uniquely cooperate with CA in killing AML cells, but not normal peripheral blood mononuclear cells. Notably, our data revealed striking phenotypical and mechanistic similarities in the apoptotic effects of MHC+CA and CUR+CA on AML cells. Yet, we show that MHC is a non-fluorescent molecule, which is an important technical advantage over CUR that can interfere in various fluorescence-based assays. Collectively, we demonstrated for the first time the antileukemic activity of MHC in combination with another phenolic compound. This type of synergistically acting combinations may represent prototypes for novel antileukemic therapy.

The aim of our work was to synthetize of a new analogue of abiraterone-thiolated abiraterone (HS-AB) and design a gold surface monolayer, bearing in mind recent advances in tuning monolayer structures and using them as efficient drug delivery systems. Therapeutic self-assembled monolayers (TSAMs) were prepared by chemically attaching HS-AB to gold surfaces. Their properties were studied by voltammetry and atomic force microscopy (AFM). A gold electrode with immobilized thioglycolic acid (HS-GA) was used for comparison. The surface concentration of HS-AB on the gold surface was 0.572 nmol/cm², determined from the area of the voltammetric reduction peaks (desorption process). The area per one molecule estimated from the voltammetry experiments was 0.291 nmol/cm². The capacity of thus prepared electrode was also tested. The calculated capacity for the HS-AB modified electrode is 2.90 μF/cm². The obtained value indicates that the monolayer on the gold electrode is quite well ordered and well-packed. AFM images show the formation of gold nanoparticles as a result of immersing the HS-AB modified gold electrode in an aqueous solution containing 1 mM HAuCl₄·3H₂O. These structures arise as a result of the interaction between the HS-AB compound adsorbed on the electrode and the AuCl₄ - ions. The voltammetric experiments also confirm the formation of gold structures with specific catalytic properties in the process of oxygen reduction.

A series of caffeic acid derivatives were synthesized via a modified Wittig reaction which is a very important tool in organic chemistry for the construction of unsaturated carbon⁻carbon bonds. All reactions were performed in water medium at 90 °C. The aqueous Wittig reaction worked best when one unprotected hydroxyl group was present in the phenyl ring. The olefinations in the aqueous conditions were also conducted with good yields in the presence of two unprotected hydroxyl groups. When the number of the hydroxyl groups was increased to three, the reaction yields were worse, and the derivatives 12 , 13 , and 18 were obtained with 74%, 37%, and 70% yields, respectively. Nevertheless, the Wittig reaction using water as the essential medium is an elegant one-pot synthesis and a greener method, which can be a safe alternative for implementation in organic chemistry. The obtained compounds were tested for their antioxidant activity, and 12 , 13 , and 18 showed the highest activities. Moreover, all synthesized compounds displayed no cytotoxicity, and can therefore be used in the pharmaceutical or cosmetic industry.

The aim of our work was the synthesis and physicochemical characterization of a unique conjugate consisting of gold nanoparticles (AuNPs) and a pharmacologically active anticancer substance abiraterone (AB). The direct coupling of AB with gold constitutes an essential feature of the unique AuNPs⁻AB conjugate that creates a promising platform for applications in nanomedicine. In this work, we present a multidisciplinary, basic study of the obtained AuNPs⁻AB conjugate. Theoretical modeling based on the density functional theory (DFT) predicted that the Au n clusters would interact with abiraterone preferably at the N-side. A sharp, intense band at 1028 cm -1 was observed in the Raman spectra of the nanoparticles. The shift of this band in comparison to AB itself agrees well with the theoretical model. AB in the nanoparticles was identified by means of electrochemistry and NMR spectroscopy. The sizes of the Au crystallites measured by XRPD were about 9 and 17 nm for the nanoparticles obtained in pH 7.4 and 3.6, respectively. The size of the particles as measured by TEM was 24 and 30 nm for the nanoparticles obtained in pH 7.4 and pH 3.6, respectively. The DLS measurements revealed stable, negatively charged nanoparticles.

An efficient methodology of the glycosylation process of a secondary plant metabolite (R-Danshensu) and its enantiomer by sugar and 2-deoxy sugar donors was developed. The overall synthesis of the new sugar derivatives involved two steps, starting from the previously synthesized protected R and S Danshensu (1 and 2). The deoxy sugar derivatives of R and S Danshensu were obtained from available tri-O-acetyl-2-deoxy-D-glucal and di-O-acetyl-2-deoxy-D-ramnal. The direct glycosylation of 1 and 2 using glycal activation by an acid catalyst in all cases led to the α-anomers of deoxy sugar derivatives with good yields. As a result, a novel group of sugar and deoxy sugar conjugates with optically pure polyphenolic acids was successfully synthesized and their cytotoxic profile against two cancer cell lines was tested. An advantageous ADME profile and antiproliferative data classified this new group of compounds as a promising scaffold for further modification of more potent and selective anticancer agents., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

An optimization of the guanidylation process by verifying the efficacy of common guanylation reagents in order to obtain the guanidine derivatives of indolo[2,3-b]quinoline has been performed. As a result, a high-yield procedure using N , N '-di-Boc- N ''-triflylguanidine was applied to synthesize the guanidine derivative of indolo[2,3-b]quinoline 1 in a gram scale for specific in vitro and in vivo biological research. Extensive studies on the antiproliferative activity against eight human tumor cell lines were completed. Compound 1 revealed the highest activity against A549 lung adenocarcinoma and MCF7 breast cancer cell lines. Thus, 1 was evaluated for the in vivo anticancer activity against 4T1 mammary gland carcinoma and KLN205 murine lung carcinoma in mouse models. The anticancer effect was observed in the KLN205 model with a 37% tumor growth inhibition at the 20 mg/kg dose. This anticancer activity of 1 was comparable to that of cyclophosphamide which inhibited murine lung tumor growth in the range of 27-43% at the dose of 100 mg/kg. The biochemistry research after 1 admission, including measurements of blood parameters like alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and urea and creatinine, were also performed.

A practical synthesis of 28a-homo-28a-selenolupane triterpenes and the corresponding selenosaponins containing d-mannose, l-arabinose, l-rhamnose, and d-idose moieties is described. Selenium containing triterpenes were obtained from the readily available 3-O-allyl-homobetulin mesylate by nucleophilic substitution with the selenocyanate ion which upon reduction of the -SeCN group afforded the free selenol. Glycosylation using classical Schmidt donors gave 1,2-trans selenosaponins as the main product as well as minute amounts of 1,2-cis isomers. This is one of the very few examples of the synthesis of selenoglycosides by direct glycosylation of free selenols. The studied selenol showed high resistance to air oxidation resulting in good stability during the synthesis of selenolupane derivatives. Cytotoxic activities of new homoselenolupane derivatives were also evaluated in vitro and revealed that some triterpenes exhibited an interesting profile against human cancer cell lines.

Due to the raising requirements of drug quality, there is an increasing need for fast liquid separations of pharmaceutical substances with high efficiency and good resolution. The ultra-high pressure liquid chromatography (UHPLC) has been considered to meet this challenge. However, it was found that this fast method has also serious disadvantages. The range of applications of the UHPLC in the analysis of pharmaceutical substances and dosage forms is currently extensively discussed. In this study we investigated the consequences of the shortening of the analysis time of the liquid chromatographic method. Bosentan, a non-peptide antagonist of human endothelin receptors, was chosen as an example in this study, due to its therapeutic importance and lack of the reported analytical methods of the drug product. Two high-performance, reversed phase liquid chromatography methods with UV detection at 220 nm were developed for this purpose. Both methods were validated and the resulting performance characteristics were compared. The first separation (method A) was achieved on Kinetex column, (2.6 μ C18 1OOA, 150 x 4.6 mm), the second-fast (method B) employed Kinetex column, (1.7 μ XB-C18 100A 50 x 3.0 mm). Both methods were performed with a buffered mobile phase containing 0.1% of triethylamine in water brought to the pH 2.5 with phosphoric acid and methanol as the solvent A and acetonitrile as the solvent B. Gradient program was used and flow rate of 0.8 mL/min and 0.4 mL/min, for the methods A and B, respectively. The methods were validated according to the ICH guidelines for specificity, precision on the specified and LOQ limits, intermediate precision, accuracy, linearity (correlation co-efficient =0.999) and robustness. The robustness was confirned using four factors: the mobile phase pH, the flow rate of the mobile phase, column temperature and the second column of the same kind. The limits of detection and quantification were established as 0.0132 and 0.1505 μg/mL for methods A and B, respectively. Both validated methods complied with the acceptance criteria. The method B was 3.5 times faster than the method A, but the method A showed much better sensitivity. The resolution between compound B and bosentan was 3.39 and 1.75 for methods A and B, respectively. The lower sensitivity limits the use of Method B, especially in the analyses at low levels of active substances (e.g., bioanalysis, validation of the cleaning procedures) and makes method A more suitable for this purpose.

Bosentan monohydrate (4- tert -butyl- N -[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl) pyrimidin-4-yl]benzene-1-sulfonamide monohydrate) is a dual endothelin receptor antagonist (ERA) applied in the treatment of pulmonary arterial hypertension. To achieve effective process control of the bosentan monohydrate synthesis, it was necessary to develop a selective and not highly time-consuming method for ultra-high performance liquid chromatography (UHPLC). The method is characterized by adequate sensitivity, reproducibility and selectivity for the determination of bosentan monohydrate and related compounds from all synthetic stages. The UHPLC separation was carried out by reversed phase chromatography on the Acquity BEH C18 column (100 mm × 2.1 mm, 1.7 µm) with a mobile phase composed of solvent A (0.1 %, v/v, acetic acid in water) and solvent B (methanol), in the gradient mode at the flow rate of 0.4 mL min -1 . Limits of detection and quantification for the compounds were ≤0.1 µg mL -1 and 0.3 µg mL -1 , respectively. The linearity for all related compounds was investigated as in the range for the active pharmaceutical ingredient (API) and as in the range for the in-process control. The developed method was validated according to the current guidelines, proving the suitability of the method for its intended purpose.

The synthesis of indolo[2,3-b]quinoline derivatives containing guanidine, amino acid or guanylamino acid substituents as well as their in vitro evaluation for the cytotoxic and antifungal activity are reported. The influence of the guanidine group on the selective cytotoxic and hemolytic properties of indolo[2,3-b]quinoline was investigated. Most of the compounds displayed a high cytotoxic activity in vitro and two of the most promising compounds (3 and 12) exhibited a high selectivity between normal and cancer cell-lines. The cytotoxic activity of compound 3 was about 600-fold lower against normal fibroblasts than against A549 and MCF-7 cancer cell lines. Novel entities acted as the DNA-intercalators when tested using a DNA-methyl green assay but demonstrated zero or low hemolytic activity in comparison to their unsubstituted analogs. The mechanism of action was studied for guanidine derivatives 3 and 12 and both compounds were found to be very effective inducers of apoptosis., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

A series of novel amino acid and dipeptide derivatives of neocryptolepine were synthesized and tested for their antimicrobial, antifungal and antiproliferative activity in vitro against cancer cell lines (KB, A549, MCF-7, LoVo) and normal mice fibroblast cells (BALB/3T3). Biological evaluation revealed that almost all of the new compounds displayed high antiproliferative activity against the tested cells and moderate to potent antibacterial activities. Interestingly, these compounds were active against Candida albicans biofilms at doses significantly lower than those required against free-floating planktonic fungal cells. The most promising compounds are derivatives with glycine and L-proline as a substituent both at 2 and at 9 position of 5H-indolo[2,3-b]quinoline. In general, these new compounds (2a, 3a, 6a and 7a) showed the highest dual action against cancer lines and infectious pathogenic microbes in vitro., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

A series of novel cyclic ureidopeptides, analogues of dermorphine/deltorphine tetrapeptide, were synthesized by solid phase peptide synthesis and/or in solution. The antinociceptive activity of N-substituted amides 1-10 was evaluated using hot-plate and tail-flick tests. Analogue 1 showed significant, stronger than morphine, antinociceptive effect after systemic applications. All analogues were also tested for their in vitro resistance to proteolysis by means of mass spectroscopy and it was found that all substituted amides 1-10 showed full stability during incubation with large excess of chymotrypsin and pepsin. Compound 1 is a lead molecule for further evaluation., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

In this article, details of crystal and molecular structures of sunitinib malate (SUM), an anticancer therapeutic, and its key synthetic intermediate are presented. Both these compounds were also characterized spectroscopically and thermally. SUM crystallizes in the monoclinic P2(1) space group with two molecules in the asymmetric part of the unit cell, whereas the intermediate crystallises in the triclinic P-1 space group with four independent molecules in the asymmetric unit. The three-dimensional structure of SUM consists of two different layers of molecules. The first one is built of the malic anions, whereas the other layer consists of more hydrophobic sunitinib molecules. This layer is formed by two types of molecules creating a herring bond-like pattern with pairs of neighboring cations forming the V-shape arrangement of molecules. The V-shaped pairs of molecules form ribbons by fitting into two neighboring V shapes. The characteristic V-shape assemble of the moieties is hold together with three C-H…F weak interactions. Besides, process-related impurities of SUM were identified and their structures confirmed by separate synthesis. These impurities were fully characterized by spectroscopic and crystallographic methods as well as by differential scanning calorimetry and thermogravimetric analysis. The H-, (13)C-, and (15)N-nuclear magnetic resonance signals were fully assigned structurally and the resulting structures were confirmed by Fourier-transformed infrared spectroscopy. It was the herein elaborated synthesis of impurity-free SUM that allowed for growing of its single crystals suitable for X-ray crystallographic studies. Comparison of the powder X-ray diffraction pattern for SUM with that derived from single-crystal X-ray crystallographic analysis indicated that SUM formed the polymorph I crystal phase, which is also encountered in its pharmaceutical formulation., (Copyright © 2012 Wiley Periodicals, Inc.)

The syntheses of neocryptolepine derivatives containing an amino acid or a dipeptide at the C-9 position and their evaluation for antitumor activity in vitro and in vivo are reported. To establish the influence of an amino acid or a peptide on the physicochemical properties of 5H-indolo[2,3-b]quinoline (DiMIQ), lipophilic and hemolytic properties were investigated. Most of the compounds displayed a high antiproliferative activity in vitro and strongly inhibited growth of tumor in mice compared to cyclophosphamide. The attachment of the hydrophilic amino acid or the peptide to the hydrophobic DiMIQ increased its hydrophilic properties and decreased its hemolytic activity. The glycylglycine conjugate (7a) was the most promising derivative. It strongly inhibited the growth of the tumor in mice (at dose 50 mg kg(-1) day(-1) it inhibited the tumor growth by 46-63% on days 11-16 and by 29-43% on days 18-23) and significantly decreased hemolytic activity and lowered the in vivo toxicity compared to DiMIQ.