7390-62-7

Usage

Uses

Different sources of media describe the Uses of 7390-62-7 differently. You can refer to the following data:
1. Irritant
2. Irritant.

Synthesis Reference(s)

Chemical and Pharmaceutical Bulletin, 21, p. 34, 1973 DOI: 10.1248/cpb.21.34

InChI:InChI=1/C5H5N5S/c6-3-2-4(8-1-7-3)10-5(11)9-2/h1H,(H4,6,7,8,9,10,11)

Upstream product

• 118-70-7 4,5,6-triaminopyrimidine 
• 17356-08-0 thiourea 
• 6974-78-3 8-bromoadenine 
• 75-15-0 carbon disulfide 
• 49721-45-1 4,5,6-triaminopyrimidine sulfate 
• 17318-18-2 2'-deoxy-8-mercaptoadenosine 

Downstream Products

• 2508-06-7 8-methylsulfanyl-7(9)H-purin-6-ylamine 
• 2508-06-7 8-(methylsulfanyl)-9H-purin-6-amine 
• 303014-70-2 (S)-6-Amino-9-[2-hydroxy-3-(trityloxy)propyl]-7H-purin-8(9H)-one 
• 303014-71-3 6-Amino-7,9-bis[(2S)-2-hydroxy-3-(trityloxy)propyl]-7H-purin-8(9H)-one 
• 696574-58-0 8-(3-methoxyphenylsulfanyl)-9H-purin-6-ylamine 
• 3001-45-4 6-amino-9-β-D-ribofuranosyl-7,9-dihydro-purine-8-thione 
• 303014-75-7 (S)-7-[(Trityloxy)methyl]-7,8-dihydro[1,3]oxazolo[3,2-e]purine-4-amine 
• 328381-23-3 (S)-3-[2-Hydroxy-3-(trityloxy)propyl]-8-(methylsulfanyl)adenine 
• 328381-25-5 (S)-9-[2-Hydroxy-3-(trityloxy)propyl]-8-(methylsulfanyl)adenine 
• 500337-60-0 8-(ethylthio)-9H-purin-6-amine 

Relevant academic research and scientific papers

A facile and efficient synthesis of d6-labeled PU-H71, a purine-scaffold Hsp90 inhibitor

PU-H71 is a purine-scaffold Hsp90 inhibitor currently undergoing late stage preclinical evaluation for the treatment of cancer. In this investigation, we present a simple method for the synthesis of d6-labeled PU-H71 for use as an internal standard to accurately quantitate the drug in biological matrices based on an LC-MS-MS method. PU-H71-d6 was synthesized in five steps using readily available 1,3-dibromopropane-d6 and is an important compound for the advancement of our clinical program. Copyright

Development of a Mitochondria-Targeted Hsp90 Inhibitor Based on the Crystal Structures of Human TRAP1

The mitochondrial pool of Hsp90 and its mitochondrial paralogue, TRAP1, suppresses cell death and reprograms energy metabolism in cancer cells; therefore, Hsp90 and TRAP1 have been suggested as target proteins for anticancer drug development. Here, we report that the actual target protein in cancer cell mitochondria is TRAP1, and current Hsp90 inhibitors cannot effectively inactivate TRAP1 because of their insufficient accumulation in the mitochondria. To develop mitochondrial TRAP1 inhibitors, we determined the crystal structures of human TRAP1 complexed with Hsp90 inhibitors. The isopropyl amine of the Hsp90 inhibitor PU-H71 was replaced with the mitochondria-targeting moiety triphenylphosphonium to produce SMTIN-P01. SMTIN-P01 showed a different mode of action from the nontargeted PU-H71, as well as much improved cytotoxicity to cancer cells. In addition, we determined the structure of a TRAP1-adenylyl-imidodiphosphate (AMP-PNP) complex. On the basis of comparative analysis of TRAP1 structures, we propose a molecular mechanism of ATP hydrolysis that is crucial for chaperone function.

Prebiotic Photochemical Coproduction of Purine Ribo- And Deoxyribonucleosides

The hypothesis that life on Earth may have started with a heterogeneous nucleic acid genetic system including both RNA and DNA has attracted broad interest. The recent finding that two RNA subunits (cytidine, C, and uridine, U) and two DNA subunits (deoxyadenosine, dA, and deoxyinosine, dI) can be coproduced in the same reaction network, compatible with a consistent geological scenario, supports this theory. However, a prebiotically plausible synthesis of the missing units (purine ribonucleosides and pyrimidine deoxyribonucleosides) in a unified reaction network remains elusive. Herein, we disclose a strictly stereoselective and furanosyl-selective synthesis of purine ribonucleosides (adenosine, A, and inosine, I) and purine deoxynucleosides (dA and dI), alongside one another, via a key photochemical reaction of thioanhydroadenosine with sulfite in alkaline solution (pH 8-10). Mechanistic studies suggest an unexpected recombination of sulfite and nucleoside alkyl radicals underpins the formation of the ribo C2′-O bond. The coproduction of A, I, dA, and dI from a common intermediate, and under conditions likely to have prevailed in at least some primordial locales, is suggestive of the potential coexistence of RNA and DNA building blocks at the dawn of life.

Ligand Conformational Bias Drives Enantioselective Modification of a Surface-Exposed Lysine on Hsp90

Targeted covalent modification of surface-exposed lysines is challenging due to their low intrinsic reactivity and high prevalence throughout the proteome. Strategies for optimizing the rate of covalent bond formation by a reversibly bound inhibitor (kinact) typically involve increasing the reactivity of the electrophile, which increases the risk of off-target modification. Here, we employ an alternative approach for increasing kinact of a lysine-targeted covalent Hsp90 inhibitor, independent of the reversible binding affinity (Ki) or the intrinsic electrophilicity. Starting with a noncovalent ligand, we appended a chiral, conformationally constrained linker, which orients an arylsulfonyl fluoride to react rapidly and enantioselectively with Lys58 on the surface of Hsp90. Biochemical experiments and high-resolution crystal structures of covalent and noncovalent ligand/Hsp90 complexes provide mechanistic insights into the role of ligand conformation in the observed enantioselectivity. Finally, we demonstrate selective covalent targeting of cellular Hsp90, which results in a prolonged heat shock response despite concomitant degradation of the covalent ligand/Hsp90 complex. Our work highlights the potential of engineering ligand conformational constraints to dramatically accelerate covalent modification of a distal, poorly nucleophilic lysine on the surface of a protein target.

HINDERED DISULFIDE DRUG CONJUGATES

The invention relates generally to disulfide drug conjugates wherein a linker comprising a sulfur-bearing carbon atom substituted with at least one hydrocarbyl or substituted hydrocarbyl is conjugated by a disulfide bond to a cysteine sulfur atom of a targeting carrier, and wherein the linker is further conjugated to a drug moiety. The invention further relates to activated linker-drug conjugates suitable for conjugation to a targeting carrier by a disulfide bond. The invention further relates to methods for preparing hindered disulfide drug conjugates.

Synthesis of carbon-11-labeled imidazopyridine- and purine-thioacetamide derivatives as new potential PET tracers for imaging of nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1)

The target tracer carbon-11-labeled imidazopyridine- and purine-thioacetamide derivatives, N-(3-[11C]methoxy-4-methoxyphenyl)-2-((5-methoxy-3H-imidazo[4,5-b]pyridin-2-yl)thio)acetamide (3-[11C]4a) and N-(4-[11C]methoxy-3-methoxyphenyl)-2-((5-methoxy-3H-imidazo[4,5-b]pyridin-2-yl)thio)acetamide (4-[11C]4a); 2-((6-amino-9H-purin-8-yl)thio)-N-(3-[11C]methoxy-4-methoxyphenyl)acetamide (3-[11C]8a) and 2-((6-amino-9H-purin-8-yl)thio)-N-(4-[11C]methoxy-3-methoxyphenyl)acetamide (4-[11C]8a), were prepared by O-[11C]methylation of their corresponding precursors with [11C]CH3OTf under basic condition (2 N NaOH) and isolated by a simplified solid-phase extraction (SPE) method in 50-60% radiochemical yields based on [11C]CO2 and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 23 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 185-555 GBq/μmol.

Imidazopyridine- and purine-thioacetamide derivatives: Potent inhibitors of nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1)

Nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) belongs to the family of ecto-nucleotidases, which control extracellular nucleotide, nucleoside, and (di)phosphate levels. To study the (patho)physiological roles of NPP1 potent and selective inhibitors with drug-like properties are required. Therefore, a compound library was screened for NPP1 inhibitors using a colorimetric assay with p-nitrophenyl 5′-thymidine monophosphate (p-Nph-5′-TMP) as an artificial substrate. This led to the discovery of 2-(3H-imidazo[4,5-b]pyridin-2-ylthio)-N-(3,4-dimethoxyphenyl)acetamide (5a) as a hit compound with a Ki value of 217 nM. Subsequent structure-activity relationship studies led to the development of purine and imidazo[4,5-b]pyridine analogues with high inhibitory potency (Ki values of 5.00 nM and 29.6 nM, respectively) when assayed with p-Nph-5′-TMP as a substrate. Surprisingly, the compounds were significantly less potent when tested versus ATP as a substrate, with Ki values in the low micromolar range. A prototypic inhibitor was investigated for its mechanism of inhibition and found to be competitive versus both substrates.

Structure-activity relationships of adenine and deazaadenine derivatives as ligands for adenine receptors, a new purinergic receptor family

Adenine derivatives bearing substituents in the 2-, N6-, 7-, 8-, and/or 9-position and a series of deazapurines were synthesized and investigated in [3H]adenine binding studies at the adenine receptor in rat brain cortical membrane preparations (rAde1R). Steep structure-activity relationships were observed. Substitution in the 8-position (amino, dimethylamino, piperidinyl, piperazinyl) or in the 9-position (2-morpholinoethyl) with basic residues or introduction of polar substituents at the 6-amino function (hydroxy, amino, acetyl) represented the best modifications. Functional evaluation of selected adenine derivatives in adenylate cyclase assays at 1321N1 astrocytoma cells stably expressing the rAde1R showed that all compounds investigated were agonists or partial agonists. A subset of compounds was additionally investigated in binding studies at human embryonic kidney (HEK293) cells, which also express a high-affinity adenine binding site. Structure-affinity relationships at the human cell line were similar to those at the rAde1R, but not identical. In particular, N 6-acetyladenine (25, Ki rat: 2.85 μM; Ki human: 0.515 μM) and 8-aminoadenine (33, Ki rat: 6.51 μM; Ki human: 0.0341 μM) were much more potent at the human as compared to the rat binding site. The new AdeR ligands may serve as lead structures and contribute to the elucidation of the functions of the adenine receptor family. 2009 American Chemical Society.

HSP90 Inhibitors Containing a Zinc Binding Moiety

The present invention relates to HSP90 inhibitors and their use in the treatment of cell proliferative diseases such as cancer. The said derivatives may further act as HDAC inhibitors.

Identification of potent water soluble purine-scaffold inhibitors of the heat shock protein 90

Hsp90 is a chaperone protein that allows cancer cells to tolerate the many components of dysregulated pathways. Its inactivation may result in targeting multiple molecular alterations and, thus, in reverting the transformed phenotype. The PU-class, a purine-scaffold Hsp90 inhibitor series, has been reported to be potent and selective against Hsp90 both in vitro and in vivo models of cancer. Here, a series of this class was synthesized and evaluated as inhibitors of the chaperone. The structure-activity relationship and selectivity for tumor Hsp90 of compounds within the series is presented. The study identifies water soluble derivatives (> 5 mM in PBS pH 7.4) of nanomolar potency (IC50 ～ 50 nM) in cellular and animal models of cancer. Binding affinities of these compounds for Hsp90 correlate well with their biological activities. When administered in vivo to mice bearing MDA-MB-468 human breast cancer xenografted tumors, these agents result in pharmacologically relevant concentrations and, accordingly, in modulation of Hsp90-client proteins in tumors.