Katarzyna Sidoryk

Synthesis and biological evaluation of new amino acid and dipeptide derivatives of neocryptolepine as anticancer agents.

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.

Physicochemical Characteristics of Sunitinib Malate and its Process-Related Impurities

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.

Searching for new derivatives of neocryptolepine: Synthesis, antiproliferative, antimicrobial and antifungal activities

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.

Synthesis of 28a-homoselenolupanes and 28a-homoselenolupane saponins

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.

Design and Molecular Modeling of Abiraterone-Functionalized Gold Nanoparticles

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 Aun 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.

Synthesis and Antioxidant Activity of Caffeic Acid Derivatives

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.

Efficient glycosylation of natural Danshensu and its enantiomer by sugar and 2-deoxy sugar donors

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.

An efficient synthesis of indolo[2,3-b]quinoline guanidine derivatives with their in vitro and in vivo study

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.

Synthesis of S-(28a-homobetulin-28a-yl) thiophosphate, thiophosphonate, and thiophosphinate

GRAPHICAL ABSTRACT ABSTRACT A concise synthesis of thiophosphate, phenylthiophosphonate, and diphenylthiophosphinate esters bearing a 28a-homolupane residue is reported. The new triterpenes were obtained from the readily available 3-O-acetylichopanol by a nucleophilic substitution of the corresponding mesylate with thiocyanate ion followed by a Michaelis–Arbuzov reaction. These results open the way to new lupane-type derivatives having a thiophosphorus moiety at the lupane core as potential anticancer compounds. Additionally, the cytotoxic activities of the new homolupane compounds were evaluated in vitro.

NaIO4/Br- as a mild system for the oxidation of 1-methyl-anthra-9,10-quinones

One of the anthraquinone classes comprises compounds with a carbonyl group. These natural or synthetic anthraquinones find their application as building blocks in the synthesis of the compounds with a biological activity. Recently, 4-substituted anthra-9,10-quinone-1-carboxylic acids (2) have been used as key intermediates in the synthesis of patented compounds (3) with anticancer activity against multidrug resistant cell lines [1, 2]. Although 2,7-dihydro-3H-dibenz[de,h]cinnolin3,7-diones (3) were successfully synthetized in a small laboratory scale, several problems were observed during the preparation of their acid intermediates (2) in a multi-gram scale.