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1

Areny jako proleki

Guzik U., Hupert-Kocurek K., Nieć A., Wojcieszyńska D.

Wiadomości Chemiczne

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2015

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[Z] 69, 3-4

255--269

EN

Nowadays, improvement of physicochemical, biopharmaceutical and pharmacokinetic properties of pharmacologically active compounds is connected with development of prodrugs. Prodrugs are defined as pharmaceutical compounds inactive in their parent form and converted either chemically or enzymatically to the active derivative in the organism. A lot of prodrugs are aromatic compounds because of benzene ring reactivity. There are two main classes of prodrugs. In the carrier-linked prodrugs, the active drug is linked to a carrier through bioreversible covalent bond removed by enzymatic or chemical reactions. The second class comprises bioprecursor prodrugs that are modified in the body to induce the functional groups. Additionally, based on the site of prodrugs conversion into their active forms, they are classified into two groups: prodrugs metabolized intracellulary and prodrugs metabolized extracellulary. Chemical or enzymatic transformation of prodrugs may occur through their reduction, decarboxylation, oxidative deamination, cyclization, phosphorylation and/or hydrolysis. These reactions enable to overcome different barriers in drug delivery through changes in aqueous solubility, chemical instability and insufficient oral adsorption. It may also cause prolonged duration of drug action. Moreover, the prodrugs strategy allows achieving brain and tumor specific targeting. Summarizing, the designing of the prodrugs seems to be one of the most promising strategies to enhance the therapeutic effect of drugs and reduction of their negative side effects.

2

Pronukleotydy o strukturze amidofosforanów i ich wewnątrzkomórkowy mechanizm aktywacji

Kulik K., Baraniak J.

Wiadomości Chemiczne

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2014

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[Z] 68, 9-10

811--831

EN

Nucleoside analogues have great therapeutic potential for the treatment of cancer and viral diseases. Once inside the cell, they are activated by a series of intracellular phosphorylation steps to produce 5’-triphosphate derivatives, which can be incorporated to DNA or RNA and act as terminators of growing polynucleotide chains [1c]. In many cases, nucleoside analogues are poor substrates for the cellular kinases needed for their activation [5]. It is clear that intracellular introduction of nucleoside analogues as phosphorylated metabolites (so called pronucleotides) could circumvent difficulties associated with the use of non-phosphorylated nucleoside analogues and could even activate inactive compounds or could increase the activity of the nucleoside analogues. However, polarity and a ready degradation by phosphatases make the use of free nucleotide analogues impractical. Therefore, much of the recent efforts have been focused on finding suitable prodrugs of nucleoside analogue monophosphates. Among the current diverse prodrug approaches, nucleoside phosphoramidate derivatives appear to be an interesting class of antiviral and anticancer agents [1c]. These prodrugs, as are devoid of negative charge, should be able to cross the cell membrane either by diffusion or utilizing transport protein [1c]. Conducted cell extract studies have provided evidence of a bioactivation mechanism that relies on enzyme-catalyzed P-N bond hydrolysis in phosphoramidate pronucleotides [1a,b]. It was assumed that phosphoramidate derivatives should generate nucleoside monophosphates inside the cell at rates that are influenced by both the nature of the amino group and the pH of the medium. Then nucleoside monophosphates should be phosphorylated in two different steps to the corresponding 5’-O-triphosphates (NTP) which can inhibit polymerase or be incorporated into the DNA strand being synthesized in the cell. Over the last decade extensive studies has been carried out to establish the mechanism of action of phosphoramidates and identification of enzymes responsible for bioactivation this pronucleotides to phosphorylated nucleosides [7, 21, 24]. Investigation of metabolism pathways provided evidence that phosphoramidase activity of Hint (histidine triad nucleotide-binding proteins) play a key role in the activation of phosphoramidate pronucleotides [23–27].

3

Przeciwnowotworowe antybiotyki enodiynowe

Boryczka S., Mól W., Jowsa A.

Wiadomości Chemiczne

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2007

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[Z] 61, 5-6

445-471

EN

Naturally occurring enediyne anticancer antibiotics derived from bacterial sources are reviewed. The enediynes represent promising chemotherapeutic agents that exhibit unprecedented molecular architecture, fascinating modes of action and extremely potent anticancer activity, more potent than other anticancer drugs. The enediynes are structurally characterized by an unsaturated core with two acetylenic groups conjugated with a double bond. All these molecules contain three impor-tant functional domains: - an enediyne ring (nine-membered or ten-membered) as a highly reactive core that generates the reactive diradicals, thus providing the fragments that damage DNA, - a triggering device which after suitable activation under physiological conditions initiates the cascade of reactions that leads to the generation of diradicals, - a delivery system that is responsible for targeting DNA. The mode of action of the enediyne antibiotics is the ability to produce single--stranded or double-stranded DNA lesions by a mechanism which involves the inter-actions with duplex DNA along specific sequences within the minor groove. This is followed by the formation of a highly reactive benzenoid diradical via Bergman or Myers-Saito cyloaromatization and abstraction of hydrogen atoms from the deoxyribose of DNA leading to site-specific DNA breaks, which induces cell apoptosis. The diradical (p-benzyne) intermediates in simple prototype enediynes were postulated by Bergman in 1972 and provided the basis for the mechanism of action of the naturally occurring enediynes. Over 20 natural enediynes antibiotics are known now. They are divided into two distinct groups; those containing a nine membered enediynes chromophore non-covalently associated with a stabilizing apoprotein (neocarzinostatin 1, kedarcidin 2, lidamycin 3, maduropeptin 4, N1999A2 5) and those containing ten membered enediyne ring (calicheamicins 6, dynemicins 7, esperamicin 8, namenamicin 9, shishijimicins 10). However, the lack of selectivity for cancer cells and toxicity of natural enediynes have complicated their use in cancer chemotherapy. Several mono-clonal antibody-enediynes and polymer-enediynes conjugates have been prepared and evaluated for clinical significance as anticancer drugs. Much effort has been devoted to the design and synthesis of new, simplified, fully synthetic analogues characterized by similar mode of action.

4

Chemiczno-enzymatyczna strategia konstrukcji proleków nukleozydowych

Kaczmarek R., Kulik K., Baraniak J.

Wiadomości Chemiczne

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2007

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[Z] 61, 5-6

417-443

EN

Several nucleoside analogues have found successful application as antiviral and anticancer agents. Their mode of action differs, but in the most general terms they have been developed as inhibitors or competitors of natural 2'-deoxynucleosides in the process of their conversion to the corresponding nucleoside-5'-triphosphates. As such, they can be incorporated into a growing viral DNA strand by a DNA polymerase resulting in chain termination. In cancer therapy, modified nucleosides, after being phosphorylated to the corresponding monophosphates, block DNA biosynthesis by deactivating nucleoside syntheses. Hence biological activity of nucleoside analogues in most cases depends on the intracellular phosphorylation by viral and/or cellular kinases to their respective mono-, di-, and triphosphate derivatives. Among the three successive activating phosphorylation steps the first one has fundamental importance as the rate-limiting step. Several different enzymes can perform this initial phosphorylation, depending on the nature of the aglycone. Also, the presence and activity of the intracellular enzymes necessary for the activation of nucleoside analogues are highly dependent on the host species, the cell type, and the stage in the cell cycle. Moreover, in many cases, nucleoside analogues are poor substrates for the cellular kinases needed for their activation. For all these reasons, intracellular nucleoside monophosphate (NMP) delivery has been considered for overcoming the first phosphorylation step. Unfortunately, NMPs themselves cannot be used as potential chemotherapeutic agents. Owing to their high polarity, these compounds are not able to penetrate cellular membrane or the blood-brain barrier easily. Therefore, in order to reduce the phosphate negative charge and enable the modified nucleotide to enter the cell, many nucleotides modified on the phos-phate moiety by so-called masking group have been synthesized. A suitable nucleotide prodrug (so-called pronucleotide) has to fulfill two requirements: i) it has to be lipophilic enough for passive diffusion of the membrane and the blood-brain barrier; ii) it should be able to deliver the nucleoside by chemical or enzymatic hydrolysis leaving a non-toxic masking group. Many strategies using various protecting groups for the phosphate moiety have been deve-loped to achieve this goal. The majority of strategies for unmasking pronucleotides that have been examined to date have involved substrate-nonspecific enzymes to remove one or more groups that are attached to the 5'MP moiety. Carboxylesterases (CEs) have attracted considerable attention, since they include bis(pivaloyloxymethyl) [(bis(POM)] and S-acyl-2-thioethyl (SATE) moieties which are initially unmasked by CE-mediated cleavage. A combination of aryl ester and amino acid phosphoramidate groups as a particular class of enzyme-labile protecting groups was developed for the delivery of antiviral nucleoside prodrugs. An endogenous phosphoramidase was responsible and necessary for the biological activity of those compounds in living cells. On the other side almost all approaches based on chemical hydrolysis reported so far were unable to deliver the nucleotide selectively exept the cycloSal approach. This review will predominantly concentrate on the different approaches to the design of nucleotide prodrugs. Keywords: prodrug, pronucleotide, nucleoside analogues, antiviral activity, anticancer acti-vity, masking groups.