A series of quinolino-fused 7-deazapurine (pyrimido[5',4':4,5]pyrrolo[3,2-f]quinoline) ribonucleosides were designed and synthesized. The synthesis of the key 11-chloro-pyrimido[5',4':4,5]pyrrolo[3,2-f]quinoline was based on the Negishi cross-coupling of iodoquinoline with zincated 4,6-dichloropyrimidine followed by azidation and thermal or photochemical cyclization. Vorbrüggen glycosylation of the tetracyclic heterocycle followed by cross-coupling or substitution reactions at position 11 gave the desired set of final nucleosides that showed moderate to weak cytostatic activity and fluorescent properties. The corresponding fused adenosine derivative was converted to the triphosphate and successfully incorporated to RNA using in vitro transcription with T7 RNA polymerase.

• Publication type
• Journal Article MeSH

A series of heterocyclic chloroquine hybrids, containing a chain of two carbon atoms at position four of the quinolinic chain and acting as a link between quinoline and several benzoyl groups, is synthesized and screened in vitro as an inhibitor of β-hematin formation and in vivo for its antimalarial activity against chloroquine-sensitive strains of Plasmodium berghei ANKA in this study. The compounds significantly reduced haeme crystallization, with IC50 values < 10 µM. The values were comparable to chloroquine's, with an IC50 of 1.50 ± 0.01 µM. The compounds 4c and 4e prolonged the average survival time of the infected mice to 16.7 ± 2.16 and 14.4 ± 1.20 days, respectively. We also studied the effect of the compounds 4b, 4c, and 4e on another important human parasite, Leishmania mexicana, which is responsible for cutaneous leishmaniasis, demonstrating a potential leishmanicidal effect against promasigotes, with an IC50 < 10 µM. Concerning the possible mechanism of action of these compounds on Lesihmania mexicana, we performed experiments demonstrating that these three compounds could induce the collapse of the parasite mitochondrial electrochemical membrane potential (Δφ). The in vitro cytotoxicity assays against mammalian cancerous and noncancerous human cell lines showed that the studied compounds exhibit low cytotoxic effects. The ADME/Tox analysis predicted moderate lipophilicity values, low unbound fraction values, and a poor distribution for these compounds. Therefore, moderate bioavailability was expected. We calculated other molecular descriptors, such as the topological polar surface area, according to Veber's rules, and except for 2 and 4i, the rest of the compounds violated this descriptor, demonstrating the low antimalarial activity of our compounds in vivo.

• Keywords
• ADMET, aminoalkylbenzoates, chloroquine, cytotoxicity, leishmaniasis, malaria,
• Publication type
• Journal Article MeSH

A new approach for synthesizing polycyclic heterofused 7-deazapurine heterocycles and the corresponding nucleosides was developed based on C-H functionalization of diverse (hetero)aromatics with dibenzothiophene-S-oxide followed by the Negishi cross-cooupling with bis(4,6-dichloropyrimidin-5-yl)zinc. This cross-coupling afforded a series of (het)aryl-pyrimidines that were converted to fused deazapurine heterocycles through azidation and thermal cyclization. The fused heterocycles were glycosylated to the corresponding 2'-deoxy- and ribonucleosides, and a series of derivatives were prepared by nucleophilic substitutions at position 4. Four series of new polycyclic thieno-fused 7-deazapurine nucleosides were synthesized using this strategy. Most of the deoxyribonucleosides showed good cytotoxic activity, especially for the CCRF-CEM cell line. Phenyl- and thienyl-substituted thieno-fused 7-deazapurine nucleosides were fluorescent, and the former one was converted to 2'-deoxyribonucleoside triphosphate for enzymatic synthesis of labeled oligonucleotides.

• MeSH
• Deoxyribonucleosides MeSH
• Cell Line, Tumor MeSH
• Nucleosides * MeSH
• Oligonucleotides MeSH
• Oxides MeSH
• Purine Nucleosides MeSH
• Pyrimidines MeSH
• Ribonucleosides * MeSH
• Zinc MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 7-deazapurine MeSH Browser
• Deoxyribonucleosides MeSH
• Nucleosides * MeSH
• Oligonucleotides MeSH
• Oxides MeSH
• Purine Nucleosides MeSH
• Pyrimidines MeSH
• Ribonucleosides * MeSH
• Zinc MeSH

The coexistence of leishmaniasis, Chagas disease, and neoplasia in endemic areas has been extensively documented. The use of common drugs in the treatment of these pathologies invites us to search for new molecules with these characteristics. In this research, we report 16 synthetic chalcone derivatives that were investigated for leishmanicidal and trypanocidal activities as well as for antiproliferative potential on eight human cancers and two nontumor cell lines. The final compounds 8−23 were obtained using the classical base-catalyzed Claisen−Schmidt condensation. The most potent compounds as parasiticidal were found to be 22 and 23, while compounds 18 and 22 showed the best antiproliferative activity and therapeutic index against CCRF-CEM, K562, A549, and U2OS cancer cell lines and non-toxic VERO, BMDM, MRC-5, and BJ cells. In the case of K562 and the corresponding drug-resistant K562-TAX cell lines, the antiproliferative activity has shown a more significant difference for compound 19 having 10.3 times higher activity against the K562-TAX than K562 cell line. Flow cytometry analysis using K562 and A549 cell lines cultured with compounds 18 and 22 confirmed the induction of apoptosis in treated cells after 24 h. Based on the structural analysis, these chalcones represent new compounds potentially useful for Leishmania, Trypanosoma cruzi, and some cancer treatments.

• Keywords
• Leishmaniasis, Trypanosoma cruzi, apoptosis, cancer, chalcone,
• MeSH
• Chagas Disease * drug therapy   MeSH
• Chalcone * pharmacology   MeSH
• Leishmania * MeSH
• Leishmaniasis * drug therapy   MeSH
• Humans MeSH
• Naphthalenes therapeutic use   MeSH
• Trypanocidal Agents * chemistry   MeSH
• Trypanosoma cruzi * MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Chalcone * MeSH
• Naphthalenes MeSH
• Trypanocidal Agents * MeSH

Inhibition of the biosynthesis of complex N-glycans in the Golgi apparatus influences progress of tumor growth and metastasis. Golgi α-mannosidase II (GMII) has become a therapeutic target for drugs with anticancer activities. One critical task for successful application of GMII drugs in medical treatments is to decrease their unwanted co-inhibition of lysosomal α-mannosidase (LMan), a weakness of all known potent GMII inhibitors. A series of novel N-substituted polyhydroxypyrrolidines was synthesized and tested with modeled GH38 α-mannosidases from Drosophila melanogaster (GMIIb and LManII). The most potent structures inhibited GMIIb (Ki =50-76 μm, as determined by enzyme assays) with a significant selectivity index of IC50 (LManII)/IC50 (GMIIb) >100. These compounds also showed inhibitory activities in in vitro assays with cancer cell lines (leukemia, IC50 =92-200 μm) and low cytotoxic activities in normal fibroblast cell lines (IC50 >200 μm). In addition, they did not show any significant inhibitory activity toward GH47 Aspergillus saitoiα1,2-mannosidase. An appropriate stereo configuration of hydroxymethyl and benzyl functional groups on the pyrrolidine ring of the inhibitor may lead to an inhibitor with the required selectivity for the active site of a target α-mannosidase.

• Keywords
• Golgi α-mannosidase II, cytotoxicity, molecular modeling, pyrrolidines, swainsonine,
• MeSH
• Aspergillus enzymology   MeSH
• Cell Line MeSH
• Drosophila melanogaster enzymology   MeSH
• Nitrogen chemistry   MeSH
• Fungal Proteins antagonists & inhibitors   metabolism   MeSH
• Golgi Apparatus enzymology   MeSH
• Inhibitory Concentration 50 MeSH
• Catalytic Domain MeSH
• Humans MeSH
• Mannosidases antagonists & inhibitors   metabolism   MeSH
• Pyrrolidines chemistry   metabolism   pharmacology   MeSH
• Molecular Docking Simulation MeSH
• Binding Sites MeSH
• Cell Survival drug effects   MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Nitrogen MeSH
• Fungal Proteins MeSH
• Mannosidases MeSH
• mannosyl-oligosaccharide 1,3 - 1,6-alpha-mannosidase MeSH Browser
• Pyrrolidines MeSH

7-Deazapurine (pyrrolo[2,3-d]pyrimidine) nucleosides are important analogues of biogenic purine nucleosides with diverse biological activities. Replacement of the N7 atom with a carbon atom makes the five-membered ring more electron rich and brings a possibility of attaching additional substituents at the C7 position. This often leads to derivatives with increased base-pairing in DNA or RNA or better binding to enzymes. Several types of 7-deazapurine nucleosides with potent cytostatic or cytotoxic effects have been identified. The most promising are 7-hetaryl-7-deazaadenosines, which are activated in cancer cells by phosphorylation and get incorporated both to RNA (causing inhibition of proteosynthesis) and to DNA (causing DNA damage). Mechanism of action of other types of cytostatic nucleosides, 6-hetaryl-7-deazapurine and thieno-fused deazapurine ribonucleosides, is not yet known. Many 7-deazaadenosine derivatives are potent inhibitors of adenosine kinases. Many types of sugar-modified derivatives of 7-deazapurine nucleosides are also strong antivirals. Most important are 2'-C-methylribo- or 2'-C-methyl-2'-fluororibonucleosides with anti-HCV activities (several compounds underwent clinical trials). Some underexplored areas of potential interest are also outlined.

• Keywords
• antivirals, cytostatics, deazapurines, nucleosides, nucleotides,
• MeSH
• Antiviral Agents chemical synthesis   chemistry   pharmacology   MeSH
• A549 Cells MeSH
• Hep G2 Cells MeSH
• HeLa Cells MeSH
• Humans MeSH
• Nucleosides chemical synthesis   chemistry   pharmacology   MeSH
• Antineoplastic Agents chemical synthesis   chemistry   pharmacology   MeSH
• Purines chemistry   MeSH
• Drug Design MeSH
• Drug Screening Assays, Antitumor MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• 7-deazapurine MeSH Browser
• Antiviral Agents MeSH
• Nucleosides MeSH
• Antineoplastic Agents MeSH
• Purines MeSH