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Journal of Medicinal Chemistry Dec 2023Novel C6-substituted pyrazolo[3,4-]pyrimidine- and C2-substituted purine-based bisphosphonate (C6-PyraP-BP and C2-Pur-BP, respectively) inhibitors of the human...
Discovery and Evaluation of C6-Substituted Pyrazolopyrimidine-Based Bisphosphonate Inhibitors of the Human Geranylgeranyl Pyrophosphate Synthase and Evaluation of Their Antitumor Efficacy in Multiple Myeloma, Pancreatic Ductal Adenocarcinoma, and Colorectal Cancer.
Novel C6-substituted pyrazolo[3,4-]pyrimidine- and C2-substituted purine-based bisphosphonate (C6-PyraP-BP and C2-Pur-BP, respectively) inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS) were designed and evaluated for their ability to block the proliferation of multiple myeloma (MM), pancreatic ductal adenocarcinoma (PDAC), and colorectal cancer (CRC) cells. Pyrazolo[3,4-]pyrimidine analogs were identified that induce selective intracellular target engagement leading to apoptosis and downregulate the prenylation of Rap-1A in MM, PDAC, and CRC cells. The C6-PyraP-BP inhibitor RB-07-16 was found to exhibit antitumor efficacy in xenograft mouse models of MM and PDAC, significantly reducing tumor growth without substantially increasing liver enzymes or causing significant histopathologic damage, usually associated with hepatotoxicity. RB-07-16 is a metabolically stable compound in cross-species liver microsomes, does not inhibit key CYP 450 enzymes, and exhibits good systemic circulation in rat. Collectively, the current studies provide encouraging support for further optimization of the pyrazolo[3,4-]pyrimidine-based GGPPS inhibitors as potential human therapeutics for various cancers.
Topics: Humans; Mice; Rats; Animals; Geranylgeranyl-Diphosphate Geranylgeranyltransferase; Multiple Myeloma; Diphosphonates; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Apoptosis; Pyrimidines; Colorectal Neoplasms; Cell Line, Tumor; Cell Proliferation; Xenograft Model Antitumor Assays
PubMed: 37982711
DOI: 10.1021/acs.jmedchem.3c01271 -
Nature Apr 2022The SARS-CoV-2 virus has infected more than 261 million people and has led to more than 5 million deaths in the past year and a half ( https://www.who.org/ )....
The SARS-CoV-2 virus has infected more than 261 million people and has led to more than 5 million deaths in the past year and a half ( https://www.who.org/ ). Individuals with SARS-CoV-2 infection typically develop mild-to-severe flu-like symptoms, whereas infection of a subset of individuals leads to severe-to-fatal clinical outcomes. Although vaccines have been rapidly developed to combat SARS-CoV-2, there has been a dearth of antiviral therapeutics. There is an urgent need for therapeutics, which has been amplified by the emerging threats of variants that may evade vaccines. Large-scale efforts are underway to identify antiviral drugs. Here we screened approximately 18,000 drugs for antiviral activity using live virus infection in human respiratory cells and validated 122 drugs with antiviral activity and selectivity against SARS-CoV-2. Among these candidates are 16 nucleoside analogues, the largest category of clinically used antivirals. This included the antivirals remdesivir and molnupiravir, which have been approved for use in COVID-19. RNA viruses rely on a high supply of nucleoside triphosphates from the host to efficiently replicate, and we identified a panel of host nucleoside biosynthesis inhibitors as antiviral. Moreover, we found that combining pyrimidine biosynthesis inhibitors with antiviral nucleoside analogues synergistically inhibits SARS-CoV-2 infection in vitro and in vivo against emerging strains of SARS-CoV-2, suggesting a clinical path forward.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; COVID-19; Cell Line; Cytidine; Drug Evaluation, Preclinical; Humans; Hydroxylamines; Nucleosides; Pyrimidines; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35130559
DOI: 10.1038/s41586-022-04482-x -
ACS Chemical Biology Jul 2021Guanine deaminase (GDA) deaminates guanine to xanthine. Despite its significance, the study of human GDA remains limited compared to other metabolic deaminases. As a...
Guanine deaminase (GDA) deaminates guanine to xanthine. Despite its significance, the study of human GDA remains limited compared to other metabolic deaminases. As a result, its substrate and inhibitor repertoire are limited, and effective real-time activity, inhibitory, and discovery assays are missing. Herein, we explore two emissive heterocyclic cores, based on thieno[3,4-]pyrimidine () and isothiazole[4,3-]pyrimidine (), as surrogate GDA substrates. We demonstrate that, unlike the thieno analog, , the isothiazolo guanine surrogate, , does undergo effective enzymatic deamination by GDA and yields the spectroscopically distinct xanthine analog, . Further, we showcase the potential of this fluorescent nucleobase surrogate to provide a visible spectral window for a real-time study of GDA and its inhibition.
Topics: Enzyme Assays; Enzyme Inhibitors; Fluorescent Dyes; Guanine Deaminase; Humans; Kinetics; Pyrimidines; Thiazoles; Thiophenes
PubMed: 34190533
DOI: 10.1021/acschembio.1c00232 -
ChemistryOpen Oct 2022A series of novel heterocyclic structures, namely 1,3-oxazines, 1,3-thiazines and 2,4-diaminopyrimidines, were designed and synthesised. The bioassay tests demonstrated...
A series of novel heterocyclic structures, namely 1,3-oxazines, 1,3-thiazines and 2,4-diaminopyrimidines, were designed and synthesised. The bioassay tests demonstrated that, among these analogues, 2,4-diaminopyridine derivatives showed significant antiproliferative activity against different human cancer cell lines (A2780, SiHa, HeLa, MCF-7 and MDA-MB-231). Pyrimidines substituted with N -(p-trifluoromethyl)aniline, in particular, displayed a potent inhibitory effect on the growth of cancer cells. Structure-activity relationships were also studied from the aspects of stereochemistry on the aminodiol moiety as well as exploring the effects of substituents on the pyrimidine scaffold.
Topics: Aniline Compounds; Cell Line, Tumor; Cell Proliferation; Cyclohexane Monoterpenes; Female; Humans; Ovarian Neoplasms; Oxazines; Pyrimidines; Thiazines
PubMed: 36200514
DOI: 10.1002/open.202200169 -
The Journal of Biological Chemistry Jan 2015Because of their high mutation rates, RNA viruses and retroviruses replicate close to the threshold of viability. Their existence as quasi-species has pioneered the...
Because of their high mutation rates, RNA viruses and retroviruses replicate close to the threshold of viability. Their existence as quasi-species has pioneered the concept of "lethal mutagenesis" that prompted us to synthesize pyrimidine nucleoside analogues with antiviral activity in cell culture consistent with an accumulation of deleterious mutations in the HIV-1 genome. However, testing all potentially mutagenic compounds in cell-based assays is tedious and costly. Here, we describe two simple in vitro biophysical/biochemical assays that allow prediction of the mutagenic potential of deoxyribonucleoside analogues. The first assay compares the thermal stabilities of matched and mismatched base pairs in DNA duplexes containing or not the nucleoside analogues as follows. A promising candidate should display a small destabilization of the matched base pair compared with the natural nucleoside and the smallest gap possible between the stabilities of the matched and mismatched base pairs. From this assay, we predicted that two of our compounds, 5-hydroxymethyl-2'-deoxyuridine and 5-hydroxymethyl-2'-deoxycytidine, should be mutagenic. The second in vitro reverse transcription assay assesses DNA synthesis opposite nucleoside analogues inserted into a template strand and subsequent extension of the newly synthesized base pairs. Once again, only 5-hydroxymethyl-2'-deoxyuridine and 5-hydroxymethyl-2'-deoxycytidine are predicted to be efficient mutagens. The predictive potential of our fast and easy first line screens was confirmed by detailed analysis of the mutation spectrum induced by the compounds in cell culture because only compounds 5-hydroxymethyl-2'-deoxyuridine and 5-hydroxymethyl-2'-deoxycytidine were found to increase the mutation frequency by 3.1- and 3.4-fold, respectively.
Topics: Anti-HIV Agents; Base Pair Mismatch; Base Pairing; Base Sequence; Deoxycytidine; Drug Design; HIV Reverse Transcriptase; HIV-1; High-Throughput Screening Assays; Molecular Sequence Data; Mutagenesis; Mutagens; Nucleic Acid Denaturation; Predictive Value of Tests; Reverse Transcriptase Inhibitors; Reverse Transcription; Thermodynamics; Thymidine; Time Factors
PubMed: 25398876
DOI: 10.1074/jbc.M114.616383 -
PloS One 2013Rapid response to chemotherapy in metastatic colorectal cancer (mCRC) patients (response within 12 weeks of chemotherapy) may increase the chance of complete resection... (Clinical Trial)
Clinical Trial
BACKGROUND
Rapid response to chemotherapy in metastatic colorectal cancer (mCRC) patients (response within 12 weeks of chemotherapy) may increase the chance of complete resection and improved survival. Few molecular markers predict irinotecan-induced rapid response and survival. Single-nucleotide polymorphisms (SNPs) in solute carrier genes are reported to correlate with the variable pharmacokinetics of irinotecan and folate in cancer patients. This study aims to evaluate the predictive role of 3 SNPs in mCRC patients treated with irinotecan and fluoropyrimidine-containing regimens.
MATERIALS AND METHODS
Three SNPs were selected and genotyped in 137 mCRC patients from a Chinese prospective multicenter trial (NCT01282658). The chi-squared test, univariate and multivariable logistic regression model, and receiver operating characteristic analysis were used to evaluate correlations between the genotypes and rapid response. Kaplan-Meier survival analysis and Cox proportional hazard models were used to evaluate the associations between genotypes and survival outcomes. Benjamini and Hochberg False Discovery Rate correction was used in multiple testing.
RESULTS
Genotype GA/AA of SNP rs2306283 of the gene SLCO1B1 and genotype GG of SNP rs1051266 of the gene SLC19A1 were associated with a higher rapid response rate (odds ratio [OR] =3.583 and 3.521, 95%CI =1.301-9.871 and 1.271-9.804, p=0.011 and p=0.013, respectively). The response rate was 70% in patients with both genotypes, compared with only 19.7% in the remaining patients (OR = 9.489, 95%CI = 2.191-41.093, Fisher's exact test p=0.002). Their significances were all maintained even after multiple testing (all p c < 0.05). The rs2306283 GA/AA genotype was also an independent prognostic factor of longer progression-free survival (PFS) (hazard ratio = 0.402, 95%CI = 0.171-0.945, p=0.037). None of the SNPs predicted overall survival.
CONCLUSIONS
Polymorphisms of solute carriers' may be useful to predict rapid response to irinotecan plus fluoropyrimidine and PFS in mCRC patients.
Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Haplotypes; Humans; Irinotecan; Linkage Disequilibrium; Liver-Specific Organic Anion Transporter 1; Male; Middle Aged; Neoplasm Metastasis; Organic Anion Transporters; Pharmacogenetics; Polymorphism, Single Nucleotide; Prospective Studies; Pyrimidines; Reduced Folate Carrier Protein; Survival Analysis; Time Factors; Treatment Outcome; Young Adult
PubMed: 24143213
DOI: 10.1371/journal.pone.0077223 -
European Journal of Medicinal Chemistry Jul 2015A library of sixteen 2nd generation amino- and amido-substituted carboranyl pyrimidine nucleoside analogs, designed as substrates and inhibitors of thymidine kinase 1...
A library of sixteen 2nd generation amino- and amido-substituted carboranyl pyrimidine nucleoside analogs, designed as substrates and inhibitors of thymidine kinase 1 (TK1) for potential use in boron neutron capture therapy (BNCT) of cancer, was synthesized and evaluated in enzyme kinetic-, enzyme inhibition-, metabolomic-, and biodistribution studies. One of these 2nd generation carboranyl pyrimidine nucleoside analogs (YB18A [3]), having an amino group directly attached to a meta-carborane cage tethered via ethylene spacer to the 3-position of thymidine, was approximately 3-4 times superior as a substrate and inhibitor of hTK1 than N5-2OH (2), a 1st generation carboranyl pyrimidine nucleoside analog. Both 2 and 3 appeared to be 5'-monophosphorylated in TK1(+) RG2 cells, both in vitro and in vivo. Biodistribution studies in rats bearing intracerebral RG2 glioma resulted in selective tumor uptake of 3 with an intratumoral concentration that was approximately 4 times higher than that of 2. The obtained results significantly advance the understanding of the binding interactions between TK1 and carboranyl pyrimidine nucleoside analogs and will profoundly impact future design strategies for these agents.
Topics: Animals; Boron Compounds; Boron Neutron Capture Therapy; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Glioma; Molecular Structure; Protein Kinase Inhibitors; Pyrimidine Nucleosides; Rats; Structure-Activity Relationship; Thymidine Kinase
PubMed: 26087030
DOI: 10.1016/j.ejmech.2015.05.042 -
Targeting mTORC1-mediated metabolic addiction overcomes fludarabine resistance in malignant B cells.Molecular Cancer Research : MCR Sep 2014MTOR complex-1(mTORC1) activation occurs frequently in cancers, yet clinical efficacy of rapalogs is limited because of the associated activation of upstream survival...
UNLABELLED
MTOR complex-1(mTORC1) activation occurs frequently in cancers, yet clinical efficacy of rapalogs is limited because of the associated activation of upstream survival pathways. An alternative approach is to inhibit downstream of mTORC1; therefore, acquired resistance to fludarabine (Flu), a purine analogue and antimetabolite chemotherapy, active agent for chronic lymphocytic leukemia (CLL) was investigated. Elevated phospho-p70S6K, also known as RPS6KB1 (ribosomal protein S6 kinase, 70kDa, polypeptide 1) (T389), an mTORC1 activation marker, predicted Flu resistance in a panel of B-cell lines, isogenic Flu-resistant (FluR) derivatives, and primary human CLL cells. Consistent with the anabolic role of mTORC1, FluR cells had higher rates of glycolysis and oxidative phosphorylation than Flu-sensitive (FluS) cells. Rapalogs (everolimus and rapamycin) induced moderate cell death in FluR and primary CLL cells, and everolimus significantly inhibited glycolysis and oxidative phosphorylation in FluR cells. Strikingly, the higher oxidative phosphorylation in FluR cells was not coupled to higher ATP synthesis. Instead, it contributed primarily to an essential, dihydroorotate dehydrogenase catalyzed, step in de novo pyrimidine biosynthesis. mTORC1 promotes pyrimidine biosynthesis by p70S6 kinase-mediated phosphorylation of CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase; Ser1859) and favors S-phase cell-cycle progression. We found increased phospho-CAD (S1859) and higher S-phase population in FluR cells. Pharmacological inhibition of de novo pyrimidine biosynthesis using N-phosphonacetyl-l-aspartate and leflunomide, RNAi-mediated knockdown of p70S6K, and inhibition of mitochondrial respiration were selectively cytotoxic to FluR, but not FluS, cells. These results reveal a novel link between mTORC1-mediated metabolic reprogramming and Flu resistance identifying mitochondrial respiration and de novo pyrimidine biosynthesis as potential therapeutic targets.
IMPLICATIONS
This study provides the first evidence for mTORC1/p70S6K-dependent regulation of pyrimidine biosynthesis in a relevant disease setting.
Topics: B-Lymphocytes; Cell Line, Tumor; Drug Resistance, Neoplasm; Glycolysis; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Oxidative Phosphorylation; Pyrimidines; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; TOR Serine-Threonine Kinases; Vidarabine
PubMed: 25061101
DOI: 10.1158/1541-7786.MCR-14-0124 -
Archives of Pharmacal Research May 2017Nucleoside analogues play an important role in antiviral, antibacterial and antineoplastic chemotherapy. Herein we report the synthesis, structural characterization and...
Nucleoside analogues play an important role in antiviral, antibacterial and antineoplastic chemotherapy. Herein we report the synthesis, structural characterization and biological activity of some 4'-C -methyl- and -phenyl dioxolane-based nucleosides. In particular, α and β anomers of all natural nucleosides were obtained and characterized by NMR, HR-MS and X-ray crystallography. The compounds were tested for antimicrobial activity against some representative human pathogenic fungi, bacteria and viruses. Antitumor activity was evaluated in a large variety of human cancer cell-lines. Although most of the compounds showed non-significant activity, 23α weakly inhibited HIV-1 multiplication. Moreover, 22α and 32α demonstrated a residual antineoplastic activity, interestingly linked to the unnatural α configuration. These results may provide structural insights for the design of active antiviral and antitumor agents.
Topics: Anti-HIV Agents; Antineoplastic Agents; Cell Line; Cell Proliferation; Crystallography, X-Ray; Dioxolanes; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HIV-1; Humans; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Purine Nucleosides; Pyrimidine Nucleosides; Structure-Activity Relationship
PubMed: 27615010
DOI: 10.1007/s12272-016-0825-6 -
Journal of Pharmacy & Pharmaceutical... 2015Years after the first report on 1,4-dihydropyridines (1,4-DHPs) and 1,2,3,4-tetrahydropyrimidines (1,2,3,4-THPMs) appeared, they are revisited as plausible therapeutic... (Review)
Review
Years after the first report on 1,4-dihydropyridines (1,4-DHPs) and 1,2,3,4-tetrahydropyrimidines (1,2,3,4-THPMs) appeared, they are revisited as plausible therapeutic agents. This is mainly due to the convenient methods that exist for their synthesis and the diverse pharmacologic properties that these scaffolds present. 1,4-Dihydropyridines and 1,2,3,4-tetrahydropyrimidines are usually regarded as analogous in several aspects. They are both prepared in multi-component reactions using very similar starting materials and synthesis protocols. This leads to common structural features between 1,4-DHPs and 1,2,3,4-THPMs, as well several related biological effects. For example, they share many pharmacological features such as analgesic, anti-tumor, antioxidant, anti-inflammatory, antitubercular, antibacterial, cardiovascular and adrenoceptor blocking activities. Numerous reviews have been devoted to the chemistry and cardiovascular effects of these compounds. However, the lack of a comprehensive literature overview on the chemotherapeutic ability of these scaffolds is behind the present attempt to provide a detailed survey of 1,4-DHPs and 1,2,3,4-THPMs and their structural features as chemotherapeutic agents.
Topics: Animals; Dihydropyridines; Humans; Pyrimidines; Structure-Activity Relationship
PubMed: 25877440
DOI: 10.18433/j3q01v