- ADENOSINE DERIVATIVES FOR USE IN THE TREATMENT OF CANCER
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The present invention relates to chemical compounds of formula (I) as defined in the amended claims, their preparation and their use in the treatment of cancer.
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Page/Page column 55; 56
(2018/01/17)
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- α,β-Methylene-ADP (AOPCP) Derivatives and Analogues: Development of Potent and Selective ecto-5′-Nucleotidase (CD73) Inhibitors
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ecto-5′-Nucleotidase (eN, CD73) catalyzes the hydrolysis of extracellular AMP to adenosine. eN inhibitors have potential for use as cancer therapeutics. The eN inhibitor α,β-methylene-ADP (AOPCP, adenosine-5′-O-[(phosphonomethyl)phosphonic acid]) was used as a lead structure, and derivatives modified in various positions were prepared. Products were tested at rat recombinant eN. 6-(Ar)alkylamino substitution led to the largest improvement in potency. N6-Monosubstitution was superior to symmetrical N6,N6-disubstitution. The most potent inhibitors were N6-(4-chlorobenzyl)- (10l, PSB-12441, Ki 7.23 nM), N6-phenylethyl- (10h, PSB-12425, Ki 8.04 nM), and N6-benzyl-adenosine-5′-O-[(phosphonomethyl)phosphonic acid] (10g, PSB-12379, Ki 9.03 nM). Replacement of the 6-NH group in 10g by O (10q, PSB-12431) or S (10r, PSB-12553) yielded equally potent inhibitors (10q, 9.20 nM; 10r, 9.50 nM). Selected compounds investigated at the human enzyme did not show species differences; they displayed high selectivity versus other ecto-nucleotidases and ADP-activated P2Y receptors. Moreover, high metabolic stability was observed. These compounds represent the most potent eN inhibitors described to date.
- Bhattarai, Sanjay,Freundlieb, Marianne,Pippel, Jan,Meyer, Anne,Abdelrahman, Aliaa,Fiene, Amelie,Lee, Sang-Yong,Zimmermann, Herbert,Yegutkin, Gennady G.,Str?ter, Norbert,El-Tayeb, Ali,Müller, Christa E.
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p. 6248 - 6263
(2015/08/24)
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- 6,8-DISUBSTITUTED PURINE COMPOSITIONS
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6,8-Disubstituted purines which can be used in drug and cosmetic compositions and/or applications are provided. These 6,8-disubstituted purines have a wide range of biological activities, including for example anti-inflammatory, anti-senescent, as well as well as other activities which are especially useful in pharmaceutical and cosmetic applications. The 6,8-disubstituted purine compounds and compositions containing such 6,8-disubstituted purines provide growth-regulatory, differentiating, antisenescent and antiaging properties with improved selectivities and efficiencies and lower toxicities than analogues known heretofore.
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Paragraph 0127
(2013/03/28)
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- Synthesis and hybridization properties of RNA containing 8-chloroadenosine.
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8-Chloroadenosine (8-Cl-Ado) has shown potential as a chemotherapeutic agent for the treatment of multiple myeloma and certain leukemias. 8-Cl-Ado treatment leads to a decrease in global RNA levels and incorporation of the analog into cellular RNA in malignant cells. To investigate the effects of 8-Cl-Ado modifications on RNA structure and function, an 8-Cl-Ado phosphoramidite and controlled-pore glass support were synthesized and used to introduce 8-Cl-Ado at internal and 3'- terminal positions, respectively. RNA oligonucleotides containing 8-chloroadenine (8-Cl-A) residues were synthesized and hybridized with complementary RNA strands. Circular dichroism spectroscopy of the resulting RNA duplexes revealed that the modified nucleobase does not perturb the overall A-form helix geometry. The thermal stabilities of 8-Cl-Ado modified duplexes were determined by UV thermal denaturation analysis and were compared with analogous natural duplexes containing standard and mismatched base pairs. The 8-Cl-Ado modification destabilizes RNA duplexes by approximately 5 kcal/mole, approximately as much as a U:U mismatched base pair. The duplex destabilization of 8-Cl-A may result from perturbation of Watson-Crick base pairing induced by conformational preferences of 8-halogenated nucleosides.
- Chen, Lisa S,Sheppard, Terry L
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p. 599 - 617
(2007/10/03)
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- 8-Chloroadenosine 3', 5'-cyclic monophosphate preparations
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The compound 8-Chloroadenosine 3',5'-cyclic phosphate is used to treat malignant tumors in warm blooded animals. Two novel single step syntheses of 8-chloroadenosine 3',5'-cyclic phosphate and other related adenine and adenosine compounds from corresponding adenosine 3', 5'-cyclic phosphate and other respective related adenosine compounds are disclosed.
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