Piotr Ruszkowski

Advancing the delivery of anticancer drugs: Conjugated polymer/triterpenoid composite.

Exemplifying the synergy of anticancer properties of triterpenoids and ion retention qualities of conjugated polymers, we propose a conducting matrix to be a reservoir of anticancer compounds. In this study, poly(3,4-ethylenedioxythiophene), PEDOT, based matrix for electrically triggered and local delivery of the ionic form of anticancer drug, oleanolic acid (HOL), has been investigated. An initial, one-step fabrication procedure has been proposed, providing layers exhibiting good drug release properties and biological activity. Investigation of obtained systems and implementation of modifications revealed another route of fabrication. This procedure was found to yield layers possessing a significantly greater storage capacity of OL(-), as evidenced by the 52% increase in the drug concentrations attainable through electro-assisted release. Examination of the biological activity of immobilised and released OL(-) molecules proved that electrochemical treatment has negligible impact on the anticancer properties of OL(-), particularly when employing the three-step procedure, in which the range of applied potentials is limited. PEDOT/OL(-) composite has been demonstrated to be a robust and cost-effective material for controlled drug delivery.

Betulin-loaded PEDOT films for regional chemotherapy

Chemotherapy is one of the most commonly used cancer treatments. Even so, it has significant adverse effects on healthy tissues. These effects can be avoided through the use of regional chemotherapy, an approach based on delivering the anti-cancer agents locally, to the site of cancer tissue accumulation. Among the different classes of biomaterials that are used as drug carriers, conducting polymers allow reversible, electrostatic immobilization and controlled release of a variety of compounds. In this work, we describe a method for producing surfaces possessing anti-cancer activity, which are a potential tool for regional chemotherapy. Our method consists of covering the surface with a conducting polymer matrix, followed by loading that matrix with cytotoxic compounds. We have chosen betulin as the model compound for this study, as it is commonly available triterpene that exhibits cytotoxicity against a variety of tumor cell lines. The presence of betulin in the polymer matrix is confirmed by SEM, EDS and IR spectroscopy. The release of betulin is carried out using two protocols, i.e. passive mode (open circuit conditions) or active (application of constant potential) mode. The biological activity of betulin that was released from the matrix is confirmed by its toxic effect against KB and MCF-7 cancer cell lines (IC50 values of 13.34±0.88μg/mL and 12.57±1.81μg/mL for KB and MCF-7, respectively). The described method of surface modification is shown to be an effective mean of producing surfaces that possess anti-cancer activity, serving as advantageous materials for regional chemotherapy applications.

16‐Membered Macrolide Lactone Derivatives Bearing a Triazole‐Functionalized Arm at the Aglycone C13 Position as Antibacterial and Anticancer Agents

A series of new C13‐triazole‐bridged and C13‐ether leucomycin analogues with a reduced aldehyde group were synthesized. Derivatives with the highest antibacterial [MIC values (S. epidermidis, S. pneumoniae): ∼2–4 μg mL−1; 2.55–5.09 μm] and cytotoxic [IC50 values (HeLa, KB, MCF‐7, A549, HepG2 cells): ∼1.35–3.70 μm] potencies were those with the best aqueous solubility and bearing a saccharide‐triazole arm at the C13 position of the aglycone. These derivatives preferentially bind at the ribosomal tunnel and show the most attractive selectivity indexes [SI; calculated relative to the human dermal fibroblast (HDF) cell line], even higher than that of the reference compound cytarabine. Results of molecular docking studies of this type of macrolide antibiotics at the ribosomal tunnel, together with experimentally determined lipophilicity and aqueous solubility values, as well as biological assay data revealed the importance of the introduced functional group at the aglycone C13 arm to the future design of anticancer and antibacterial drug candidates. Our results clearly indicate that the high antibacterial and anticancer activities of these types of macrolides do not necessarily depend on the presence of the aldehyde group at the aglycone lactone ring.

Oleanolic Acid A-lactams Inhibit the Growth of HeLa, KB, MCF-7 and Hep-G2 Cancer Cell Lines at Micromolar Concentrations

Oleanolic acid ketones, oximes, lactams and nitriles were obtained. Complete spectral characterizations (IR, (1)H NMR, (13)C NMR, DEPT and MS) of the synthesized compounds are presented. The derivatives had oxo, hydroxyimino, lactam or nitrile functions at the C-3 position, an esterified or unmodified carboxyl group at the C- 17 location and, in some cases, an additional oxo function at the C-11 position. The new compounds were tested for cytotoxic activity on the HeLa, KB, MCF-7 and Hep-G2 cancer cell lines with the application of MTT [3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] test. Among the tested compounds, some oximes and all lactams proved to be the most active cytotoxic agents. These triterpenes significantly inhibited the growth of the HeLa, KB, MCF-7 and Hep-G2 cancer cell lines at micromolar concentrations.

3′-O- and 5′-O-Propargyl Derivatives of 5-Fluoro-2′-Deoxyuridine: Synthesis, Cytotoxic Evaluation and Conformational Analysis

ABSTRACT A series of new 3′-O- and 5′-O-propargyl derivatives of 5-fluoro-2′-deoxyuridine (1–4) was synthesized by means of propargyl reaction of properly blocked nucleosides (2,4), followed by the deprotection reaction with ammonium fluoride. The synthesized propargylated 5-fluoro-2′-deoxyuridine analogues (1–4) were evaluated for their cytotoxic activity in three human cancer cell lines: cervical (HeLa), oral (KB) and breast (MCF-7), using the sulforhodamine B (SRB) assay. The highest activity and the best SI coefficient in all of the investigated cancer cells were displayed by 3′-O-propargyl-5-fluoro-2′-deoxyuridine (1), and its activity was higher than that of the parent nucleoside. The other new compounds exhibited moderate activity in all of the used cell lines. GRAPHICAL ABSTRACT

Immobilization of Zidovudine Derivatives on the SBA-15 Mesoporous Silica and Evaluation of Their Cytotoxic Activity.

Novel zidovudine derivatives, able to be covalently conjugated to silica surface, have been obtained and grafted to SBA-15 mesoporous silica. Cytotoxic activity of the hybrid organic-inorganic (zidovudine derivatives-silica) systems against HeLa and KB cell lines has been analyzed. Addition of folic acid had a positive influence on the cytotoxicity. Up to 69% of HeLa and 65% of KB tumor cells growth inhibition has been achieved at low silica concentration used (10 μg/mL).

Synthesis of Novel 2′,3′-Didehydro-2′,3′-dideoxyinosine Phosphoramidate Prodrugs and Evaluation of their Anticancer Activity

An efficient synthesis of 4-chlorophenyl N-alkyl phosphoramidates of 2 ′,3 ′-didehydro-2 ′,3 ′-dideoxyinosine employing 4-chlorophenyl phosphoroditetrazolide as a phosphorylating agent is reported. Improved method for the synthesis of 2 ′,3 ′-didehydro-2 ′,3 ′-dideoxyinosine starting from inosine is also described. The synthesized phosphoramidates 11–18 were examined for their cytotoxic activity in three human cancer cell lines: cervical (HeLa), oral (KB), and breast (MCF-7) employing sulforhodamine B assay. The highest activity in all investigated cancer cell lines was displayed by phosphoramidate 13 with N-n-propyl substituent.

Synthesis and cytotoxic activity of novel acyclic nucleoside analogues with functionality in click chemistry

ABSTRACT We describe synthesis of novel acyclic nucleoside analogues which are building blocks for CuAAC reaction and their activity against two types of human cancer cell lines (HeLa, KB). Three of chosen compounds show promising cytotoxic activity. Synthesis pathway starting from simple and easily accessible substrates employing DMT or TBDPS protective groups is described. Adenosine and thymidine analogues containing alkyne moiety and adenosine analogue containing azido group were synthesized. The obtained units showed ability of forming triazole motif under the CuAAC reaction conditions. GRAPHICAL ABSTRACT

Enhancing anticancer activity through the combination of bioreducing agents and triterpenes

AIM Triterpenes are natural compounds, whose wide biological activity predestines them for application as promising new chemotherapeutics. In this paper, we report the results of our investigations into the substitution of oleanolic acid with aromatic and nitroaromatic moieties acting as bioreducing agents. RESULTS The process of reduction of nitro groups was investigated through cyclic voltammetry, UV-Vis and electron paramagnetic resonance spectroelectrochemistry. The cytotoxic activity against selected cancer cell lines was determined, showing a significant increase in cytotoxicity when the triterpene is equipped with a nitroaromatic moiety. CONCLUSION We believe this approach to the functionalization is promising in terms of enhancing anticancer activity. We also indicate electrochemical techniques as advantageous preclinical screening methods for the identification of cytotoxic agents.

Cytotoxic and Trypanocidal Activities of Cinchona Alkaloid Derivatives

A series of 27 cinchona alkaloid derivatives (1f–w, 2a–e and 3a–d) were investigated for their cytotoxic and trypanocidal activities using seven different cancer cell lines (KB, HeLa, MCF‐7, A‐549, Hep‐G2, U‐87 and HL‐60), two normal cell lines (HDF and CHO) and bloodstream forms of Trypanosoma brucei brucei, respectively. Four compounds (1u, 1w, 2e and 3d) were identified with promising cytotoxic activity with 50% growth inhibition (GI50) values below 10 μM. Two (2e and 3d) of the four compounds also exhibited potent anti‐trypanosomal activity with GI50 values of 0.3–0.4 μM. All four active compounds represented derivatives modified at their C‐9 hydroxy group. With respect to anti‐proliferative activity and selectivity, 2e (epi‐N‐quinidyl‐N′‐bis(3,5‐trifluoromethyl)phenylthiourea) proved to be the most promising derivative for both cancer cells and bloodstream forms of T. b. brucei. The cytotoxic activity of compounds 1u, 1w, 2e and 3d was attributed to their ability to induce apoptosis in cancer cells. The results demonstrate the potential of cinchona alkaloid derivatives as novel anti‐cancer and anti‐trypanosome drug candidates.