1,721,247 research outputs found
Thioridazine derivatives and their use for the treatment of cancer
No full textThe present invention relates to novel thioridazine analog compds. of formula (I): wherein R1 is OCH3 or NH2 , particularly suitable to be used in the treatment of pediatric acute myeloid leukemia harboring the t(6;11)(q27;q23) KMT2A/AFDN rearrangement
DNA minor groove alkylating agents structurally related to distamycin A
No full textA review with 39 refs. Analogs of naturally occurring antitumor agents, such us distamycin A, which bind in the minor groove of DNA, represent a new class of antineoplastic compds. currently under investigation. Distamycin A has attracted researchers attention not only for its biol. activity, but also for its non-intercalative binding to the minor groove of double-stranded B-DNA, where it forms a strong reversible complex preferentially at the nucleotide sequences consisting of 4 - 5 adjacent AT base pairs. Distamycin has also been used as a DNA sequence-selective vehicle for the delivery of alkylating functions to DNA targets, leading to a sharp increase in cytotoxicity, in comparison to that of distamycin alone. In the last few years, several hybrid compds., in which known antitumor derivs. or simple active moieties of known antitumor agents have been tethered to distamycin frames, have been designed, synthesized and tested. Several efforts have been made to modify the DNA sequence selectivity and stability of distamycin; structural modifications have been based on replacement of pyrrole by other heterocycles and/or benzoheterocycles resulting in a novel class of minor groove binding mols. called lexitropsins. The role of the amidino moiety has also been studied by substitution with various groups, including ionizable, acid or basic and non-ionizable groups. The synthesis of a hybrid derived from combining distamycin A and a naturally occurring alkylating agent structurally related to pyrrolo [2,1-c][1,4] benzodiazepine group, such as anthramycin and DC-81, has been also reported. Several classes of distamycin derivs. that have been reported in the published literature and in recent patent fillings have been described in this review article
Pharmaceutically active compounds and methods of use
No full textNew fused thiophene compounds are provided and methods of using those compounds for a variety of therapeutic indications. Compounds of the invention are particularly useful for treatment of neuropathic pain
Leukocyte P2 receptors: A novel target for anti-inflammatory and anti-tumor therapy
No full textP2 receptors are a class of plasma membrane receptors ligated by extracellular nucleotides and expressed ubiquitously throughout the body. Two main families are known: P2X and P2Y. P2X are ligand (ATP)-gated channels, while P2Y are G-protein-coupled seven membrane-spanning receptors. The P2X and the P2Y subfamilies comprise seven and eight members, respectively. While ATP is the only known physiological ligand of P2X receptors, P2Y receptors are known to be also activated by ADP, UTP, UDP and UDP-glucose in a subtype-specific manner. Several P2 subtypes are expressed by leukocytes where they have been implicated in a host of different responses ranging from chemotaxis to differentiation, from proliferation to cytotoxicity, from secretion of inflammatory mediators to cell fusion. However, until recently there was no in vivo proof of the participation of P2 receptors in inflammatory or proliferative disorders and, in addition, few pharmacological modulators of P2 function were available. During the last two years animal and human studies have produced preliminary but nevertheless compelling evidence in support of an important function of P2 receptors in inflammation and hematological tumors. Importantly, selective blockers of these receptors have been synthesized, thus paving the way to the possible development of P2-targeted anti-inflammatory and anti-tumoral therapies
Benzoyl nitrogen mustard derivatives of benzoheterocyclic analogues of netropsin: Synthesis and biological activity
No full textSynthesis, DNA binding properties and biol. activity of a series of bis-benzoheterocycle derivs. , structurally related to the natural dipyrrole antitumor agent netropsin, and tethered to a benzoyl nitrogen mustard (BAM) as alkylating moiety is reported and structure-activity relationships detd. These compds. have been evaluated for sequence selective alkylating properties and cytotoxicity against murine L1210 and human K562 leukemia cells. Using as target sequence a portion of the long terminal repeat of the type-1 human immunodeficiency virus, we found that these compds. induce similar patterns of DNA fragmentation. In addn., the results obtained indicate that all synthesized compds. retain a good antiproliferative activity in the submicromolar range, and generally are more active against L1210 than K562 cells. With respect to both these cell lines, compds. showed the greatest potency, ranging from 0.3 to 1 M, while some other compds. exhibit the lowest activity (IC50 = 2 - 12 M). Among compds., the deriv. was found to be the most potent member of this class and it is 5 and 10-fold less active than the bis-pyrrole counterpart it against K562 and L1210 cell lines, resp. For another compd., the substitution of the C-terminus benzofurane with N-methylindole and indole led to a decrease in cytotoxicity, which is more evident against the K562 cell line. Finally, differences were found among compds. in induction of K562 differentiation. Some of them are potent inducers of erythroid differentiation of K562 cells, and could be proposed for differentiation anti-cancer therapy
Preparation of combretastatin derivatives with cytotoxic activity
No full textombretastatin derivs., such as I [R1, R2, R3, R4 = H, OH, OMe, OCH2O, NO2, F, Cl, Br, OPO3H2, OCH2OPO3H2 and their disodium salts; R1R2 = CR8:CR9X; R8, R9 = H, OH, NO2, NH2, halo, OPO3H2, OCH2OPO3H2 and their disodium salts; X = O, S, N; Y = CR5:CR6-cis or trans; II, III; R5, R6 = H, halo; R7 = H, OMe, SO2Ph; Ar = aryl, heterocyclyl], are prepd. and evaluated for their cytotoxic activity. The prepd. compds., though chem. related to the structure of cis/trans-combretastatin, do not always bind tubulin, but nevertheless exhibit cytotoxic activity of interest in the oncol. field as anticancer and/or antiangiogenic agents. Thus, combretastatin deriv. IV was prepd. via a multistep synthetic sequence starting from 2-thienylcarboxaldehyde, diethylsuccinate and (3,4,5-trimethoxybenzyl)triphenylphosphonium bromide. IV exhibited cytotoxicity against bovine microcirculatory endothelial cells (IC50 = 87±1 mM)
Allosteric modulation of A1-adenosine receptor: A review
No full textAllosteric modulators of adenosine receptors represent an alternative to direct-acting adenosine agonists and nucleoside uptake blockers, preferably those can selectively modulate the response to adenosine in only those organs or localized areas of a given organ in which production of adenosine is increased. Allosteric enhancers at the adenosine A1 receptor have received attention as anti-arrhythmic cardiac agents, and, more recently, as anti-lipolytic agents. In addition, this class of compounds has therapeutic potential as analgesics and neuroprotective agents
Pharmaceutically active compounds and methods for use
No full textNew fused thiophene compounds are provided and methods of using those conmpounds for a variety of therapeutic indications. Compounds of the invention are particulary useful for treatment of neuropathic pai
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