Ivan Butula

Primaquine-NSAID twin drugs: Synthesis, radical scavenging, antioxidant and Fe2+ chelating activity.

Primaquine-NSAID twin drugs: Synthesis, radical scavenging, antioxidant and Fe2+ chelating activity Novel primaquine conjugates with non-steroidal anti-inlammatory drugs (PQ-NSAIDs, 4a-h) were prepared, fully chemically characterized and screened for radical scavenging and antioxidant activities. The synthetic procedure leading to twin drugs 4a-h involved two steps: i) preparation of NSAID benzotriazolides 3a-h from the corresponding NSAID (ibuprofen, ketoprofen, fenoprofen, ketoprofen hydroxy and methylene analogues, diclofenac or indomethacin) and benzotriazole carboxylic acid chloride (BtCOCl, 1), ii) reaction of intermediates 3a-h with PQ. The prepared PQ-NSAIDs exerted moderate activities in the DPPH free radical test and β-carotene-linoleic acid assay. Moreover, ketoprofen derivatives 4d and 4b demonstrated a notable Fe2+ chelating ability as well. On the other hand, negligible antiproliferative and antituberculotic effects of conjugates 4a-h were observed. Dvojni lijekovi primakina i nesteroidnih protuupalnih lijekova: Sinteza, hvatanje slobodnih radikala, antioksidativno djelovanje i keliranje Fe2+ iona U radu je opisana sinteza novih konjugata primakina s nesteroidnim protuupalnim lijekovima (PQ-NSAIDs, 4a-h), njihova potpuna karakterizacija te testiranje sposobnosti hvatanja slobodnih radikala i antioksidativnog djelovanja. Sintetski postupak za pripravu dvojnih lijekova 4a-h uključuje dva koraka: i) pripravu NSAID-benzotriazolida 3a-h iz odgovarajućih nesteroidnih protuupalnih lijekova (ibuprofena, ketoprofena, fenoprofena, hidroksi i metilenskih analoga ketoprofena, diklofenaka i indometacina) i klorida 1-benzotriazol karboksilne kiseline (BtCOCl, 1), ii) reakciju intermedijera 3a-h s primakinom. Novi PQ-NSAID konjugati pokazuju umjerenu sposobnost hvatanja slobodnih radikala u DPPH testu te umjereno antioksidativno djelovanje u pokusu s β-karotenom i linoleinskom kiselinom. Osim toga, derivati ketoprofena 4d i 4b imaju primjetnu sposobnost keliranja Fe2+ iona. Svi konjugati 4a-h pokazuju vrlo slabo antiproliferativno i antituberkulotsko djelovanje.

Macromolecular prodrugs. VIII. Synthesis of polymer-gemfibrozil conjugates.

Gemfibrozil is covalently linked to two similar polymers: poly[alpha,beta-(N-2-hydroxyethyl-DL-aspartamide)] and poly[alpha,beta-(N-3-hydroxypropyl-DL-aspartamide)]. The synthesised polymer drug conjugates differ in average molecular mass, type of covalent bonding, length of spacer, drug-loading and solubility.

Synthesis and biological evaluation of O-methyl and O-ethyl NSAID hydroxamic acids

This paper reports the synthesis of O-methyl and O-ethyl NSAID hydroxamic acids, their antimicrobial activities, and their ability to inhibit urease and soybean lipoxygenase activities. Ibuprofen and fenoprofen hydroxamic acids with free hydroxy groups present the highest antimicrobial activity, while indomethacin and diclofenac analogs show significantly lower antimicrobial activity. Diclofenac hydroxamic acid 4e exerts the highest anti-urease activity. Indomethacin O-ethyl hydroxamic acid 3h and ibuprofen O-benzyl hydroxamic acid 4b exert significant inhibitory activities on soybean lipoxygenase. Fenoprofen and indomethacin O-ethyl hydroxamic acids 3b and 3h and diclofenac and indomethacin O-benzyl analogs 4g and 4i highly inhibit lipid peroxidation. The highest antioxidant activity was shown by fenoprofen derivative 3b.

Macromolecular prodrugs. VII. Polymer-dopamine conjugates

Abstract Dopamine (3,4-dihydroxyphenetylamine, DOP) was covalently linked to poly[ α , β -( N -2-hydroxyethyl-DL-aspartamide)] (PHEA) and styrene-maleic anhydride copolymer (SMA) in order to prepare polymeric prodrugs as a potentially more stable form of dopamine. Release of active substance from polymer drug conjugates was studied in different buffer solutions at 37 ± 0.1°C. The following rate constants for PHEA-DOP were obtained: k = 2.50 × 10 −2 min −1 (pH = 1.2); k = 4.09 × 10 −3 min −1 (pH = 7.4), and k = 1.71 × 10 −2 min −1 (pH = 9.2). The rate constants for SMA-DOP were: k = 2.27 × 10 −3 min −1 (pH = 7.4) and k = 7.98 × 10 −3 min −1 (pH = 9.2).

Cytostatic and Antiviral Activity Evaluations of Hydroxamic Derivatives of Some Non-steroidal Anti-inflammatory Drugs

Non‐steroidal anti‐inflammatory drugs (NSAID) pharmacophores are interesting in designing potential anticancer drugs. Indeed, numerous experimental, epidemiologic and clinical studies suggest that NSAIDs are promising anticancer drugs. Herein, NSAID hydroxamic acids 3a‐i were prepared by a new synthetic procedure and evaluated for their antiviral and cytostatic activity against malignant tumor cell lines and normal human fibroblasts (WI38). Antiviral activity evaluation results indicated that 3f had only a minor activity against the influenza virus A/H1N1 subtype with a selectivity index of 7–10. On the other hand, the results of the in vitro cytostatic activity evaluations revealed that the majority of NSAID hydroxamic acid derivatives 3a–i exhibited a strong non‐specific antiproliferative effect at the highest concentration (100 μm) on the tested cell line panel. Only compounds 3b, 3e and 3i exerted a differential dose‐dependent inhibitory activity against the growth of HeLa cells (p < 0.05) at concentration 10 μm. Among those three compounds, only compound 3b showed a selective cytostatic effect on HeLa in comparison with normal fibroblasts.

Macromolecular prodrugs V. Polymer-broxuridine conjugates

Abstract Broxuridine (BrdU) was covalently bound to α,β-poly[(2-hydroxyethyl)- dl -aspartamide](PHEA) and α,β-poly[(2-aminoethyl)-DL-aspartamide]-α,β-poly[(2-hydroxyethyl)-DL-aspartamide](PAHA). BrdU was first chemically modified to 3′- O -acetyl-5′- O -chloroformyl-5-bromo-2′-deoxyuridine (AcCBrdU) and 3′- O -acetyl-5′- O -phosphooxydichloride-5-bromo-2′-deoxyuridine (AcPBrdU). These compounds were bound to PHEA by carbonate and phosphodiester linkages, respectively. 5-Bromo-2′-deoxyuridine 5′-monophosphate (PBrdU) was linked to PAHA by an amide type bond. Neuroepithelial cells were used as a model system to assess the suitability of the conjugated BrdU for cell proliferation. Parallel experiments were performed with unconjugated BrdU and the extent of incorporation into DNA was determined by immunocytochemistry using an BrdU antibody. The results from these studies suggest that conjugated BrdU can be used as an alternative to currently used means of BrdU delivery.

Novel lipophilic hydroxyurea derivatives: Synthesis, cytostatic and antiviral activity evaluations

The novel hydroxyurea derivatives of l‐ and d‐amino acid amides 5a–l were prepared by aminolysis of N‐(1‐benzotriazolecarbonyl)‐amino acid amides 4a–f with O‐benzylhydroxylamine and N‐methylhydroxylamine and evaluated for their antiviral and cytostatic activity against malignant tumor cell lines and normal human fibroblasts. Compounds 5a, 5c, 5e and 5k showed the highest antiproliferative effects against all tumor cell lines tested. The strongest non‐specific cytostatic activities against HeLa cells were affected by compounds 5a, 5c, 5e and 5k on MCF‐7 cells by 5c, 5e and 5k and MIA PACa‐2 cells by 5c and 5k. Differential effects at micromolar concentrations were observed for compounds 5a, 5c, 5e, 5k and 5l in Hep G2 cells, for compounds 5c, 5e, 5k and 5l in PC‐3 cells and for compounds 5e, 5k and 5l in SW 620 cells.

Preparation and in vivo effect of microencapsulated cholinotoxin

Abstract Long-term controlled release of a neurotoxin was achieved in vivo by microencapsulating the cholinotoxin in a poly(lactic acid) matrix. A dose of 0.59 nmol of the toxin (in 20 mg of microcapsules) produced a significant reduction in choline acetyltransferase (ChAT) activity in the cortex without affecting other brain structures.

Synthesis, antibacterial and cytotoxic activity evaluation of hydroxyurea derivatives

5 Synthesis and biological evaluation of a series (N = 16) of cyclic and acyclic hydroxyurea derivatives, including benzotriazole-, isocyanuric acid- and biuret-containing compounds, are disclosed. 1-N-(benzyloxycarbamoyl)benzotriazole was used as a benzyloxyisocyanate donor, a useful intermediate in the preparation of substituted hydroxyurea. Antibacterial activities of synthesized hydroxyurea derivatives were tested on three E. coli strains, i.e., a strain susceptible to antibiotics, a strain resistant to macrolide antibiotics and a strain resistant to aminoglycoside antibiotics. Six compounds (three acyclic and three cyclic hydroxyureas) showed growth inhibition of the tested E. coli strains, with different specificity toward each strain. Results of the cytotoxic activity evaluation revealed that twelve out of sixteen test compounds were cytotoxic to human acute monocytic leukemia THP-1 and/or human acute T cell leukemia Jurkat cell line. 1-(N-hydroxycarbamoyl) benzotriazole () increased the metabolic activity of both cell lines. Two compounds, 1-(N-hydroxycarbamoyl) benzotriazole (5) and N,N’,N’’-trihydroxybiuret (15), were identified as potential NO donors.