22917-85-7Relevant articles and documents
The discovery of purine-based agents targeting triple-negative breast cancer and the αB-crystallin/VEGF protein–protein interaction
Fosu-Mensah, Nelly A.,Jiang, Wen,Brancale, Andrea,Cai, Jun,Westwell, Andrew D.
, p. 182 - 202 (2019/01/04)
Oestrogen receptor-negative breast cancer, particularly subtypes such as triple-negative breast cancer (TNBC, around 10–15% of cases), are characterised by poor long-term survival, poor response to therapy and early progression to metastasis. Purine-based compounds represent a privileged scaffold in anticancer drug design, with several clinically approved and experimental agents in clinical development comprising a purine core structure. In this study, a series of new purine-based compounds were synthesised; seven of the new analogues were found to significantly reduce the in vitro viability of TNBC cell lines (MDA-MB-231 and MDA-MB-436) with IC50 values of ≤50 μM. In previous work, we have proposed a new concept for targeting angiogenesis driving TNBC progression, by disrupting the protein–protein interaction between the molecular chaperone αB-crystallin (CRYAB) and VEGF. Since previous clinical studies applying anti-VEGF therapy to TNBC patients have met with limited success, we were interested to test our most promising purine analogues against CRYAB/VEGF, using a custom-designed cell-based CRYAB/VEGF165 interaction assay platform. Analogues 4e and 4f significantly reduced the interaction between CRYAB/VEGF165, and compound 4e (100 μM) was also found to decrease the levels of soluble VEGF expressed by MDA-MB-231 cells by 40%. In conclusion, these promising early activity profiles warrant further investigation to validate this concept.
HETEROCYCLIC GTP CYCLOHYDROLASE 1 INHIBITORS FOR THE TREATMENT OF PAIN
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Page/Page column 58, (2011/04/19)
The present invention relates to the field of small molecule heterocyclic inhibitors of GTP cyclohydrolase (GCH-I), or a tautomer, prodrug, or pharmaceutically acceptable salt thereof. The invention also features pharmaceutical compositions of the compounds and the medical use of these compounds for the treatment or prevention of pain (e.g., inflammatory pain, nociceptive pain, functional pain, or neuropathic pain).
Process for the preparation of 9-substituted guanine derivatives
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, (2008/06/13)
A process for the preparation of 9-substituted quanine derivatives of general formula (I), in which R is C1 -C4 -alkyl optionally substituted with one or more hydroxy groups, or R is (α), benzyl, ribosyl, 2'-deoxyribosyl or (CH2)n -OR1 where n is 1 or 2, and R1 is CH2 CH2 OH or (β) or salts thereof, in which a 1-substituted5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide of general formula (III), where R has the same meaning as in formula (I), is cyclized: a) by treatment with a heavy metal salt of the group of Cu-, Ag-, Pb- and Hg-salts in an aqueous alkaline medium containing at least for equivalents of OH-ions at a temperature form about 0° C. to the reflux temperature, or b) by treatment with a peroxy compound in an aqueous alkaline medium at a temperature of about 0°-30° C., whereafter (I) is isolated by treatment with a acid and, if desired, is converted into a salt. The invention further comprises intermediates for use in the preparation of the above-mentioned compounds.