Chemical synthesis of 4’-thio and 4’-sulfinyl pyrimidine nucleoside analogues

Analogues of the canonical nucleosides required for nucleic acid synthesis have a longstanding presence and proven capability within antiviral and anticancer research. 4’-Thionucleosides, that incorporate bioisosteric replacement of furanose oxygen...

Photoredox chemistry in the synthesis of 2-aminoazoles implicated in prebiotic nucleic acid synthesis

A direct link from cyanamide to cyanosulfidic chemistry via thiourea was demonstrated. 2-Aminoazoles were generated by photoredox cycling under prebiotically plausible conditions.

Long non-coding RNA GAS5 acts as proliferation “brakes” in CD133+ cells responsible for tumor recurrence

Presence of quiescent, therapy evasive population often described as cancer stem cells (CSC) or tumor initiating cells (TIC) is often attributed to extreme metastasis and tumor recurrence. This population is typically enriched in a tumor as a result of microenvironment or chemotherapy induced stress. The TIC population adapts to this stress by turning on cell cycle arrest programs that is a “fail-safe” mechanism to prevent expansion of malignant cells to prevent further injury. Upon removal of the “stress” conditions, these cells restart their cell cycle and regain their proliferative nature thereby resulting in tumor relapse. Growth Arrest Specific 5 (GAS5) is a long-non-coding RNA that plays a vital role in this process. In pancreatic cancer, CD133+ population is a typical representation of the TIC population that is responsible for tumor relapse. In this study, we show for the first time that emergence of CD133+ population coincides with upregulation of GAS5, that reprograms the cell cycle to slow proliferation by inhibiting GR mediated cell cycle control. The CD133+ population further routed metabolites like glucose to shunt pathways like pentose phosphate pathway, that were predominantly biosynthetic in spite of being quiescent in nature but did not use it immediately for nucleic acid synthesis. Upon inhibiting GAS5, these cells were released from their growth arrest and restarted the nucleic acid synthesis and proliferation. Our study thus showed that GAS5 acts as a molecular switch for regulating quiescence and growth arrest in CD133+ population, that is responsible for aggressive biology of pancreatic tumors.

Antimicrobial Drug Interactions: Systematic Evaluation of Protein and Nucleic Acid Synthesis Inhibitors

Antimicrobial multidrug resistance and its transmission among strains are serious problems. Success rate is decreased and treatment options are narrowed due to increasing bacterial multidrug resistance. On the other hand, the need for long-term efforts to discover new antibiotics and difficulties finding new treatment protocols make this problem more complex. Combination therapy, especially with synergistic use of antimicrobials is a rational treatment option with huge benefits. Thus, screening antibiotic interactions is crucial for finding better treatment options. Clinicians currently use combinatorial antibiotic treatment as an effective treatment option. However, antibiotics can show synergistic or antagonistic interactions when used together. In our study, we aimed to investigate interactions of antibiotics with different mechanisms of action. Antibiotics, which act as protein synthesis inhibitors (P) and nucleic acid synthesis inhibitors (N) were used in our study. We tested 66 (PN), 15 (NN), and 55 (PP) drug pairs on the Escherichia coli strain. The Loewe additivity model was used and alpha scores were calculated for analysis of interactions of drug combinations. Drug interactions were categorized as synergistic or antagonistic. Accordingly, pairwise combinations of protein synthesis inhibitors (PP) showed stronger synergistic interactions than those of nucleic acid synthesis inhibitors (NN) and nucleic acid synthesis–protein synthesis inhibitors (PN). As a result, the importance of mechanisms of action of drugs is emphasized in the selection of synergistic drug combinations.

Long non-coding RNA GAS5 acts as proliferation “brakes” in CD133+ cells responsible for tumor recurrence

Presence of quiescent, therapy evasive population often described as cancer stem cells (CSC) or tumor initiating cells (TIC) is often attributed to extreme metastasis and tumor recurrence. This population is typically enriched in a tumor as a result of microenvironment or chemotherapy induced stress. The TIC population adapts to this stress by turning on cell cycle arrest programs that is a “fail-safe” mechanism to prevent expansion of malignant cells to prevent further injury. Upon removal of the “stress” conditions, these cells restart their cell cycle and regain their proliferative nature thereby resulting in tumor relapse. Growth Arrest Specific 5 (GAS5) is a long-noncoding RNA that plays a vital role in this process. In pancreatic cancer, CD133+ population is a typical representation of the TIC population that is responsible for tumor relapse. In this study, we show for the first time that emergence of CD133+ population coincides with upregulation of GAS5, that reprograms the cell cycle to slow proliferation by inhibiting GR mediated cell cycle control. The CD133+ population further routed metabolites like glucose to shunt pathways like pentose phosphate pathway, that were predominantly biosynthetic in spite of being quiescent in nature but did not use it immediately for nucleic acid synthesis. Upon inhibiting GAS5, these cells were released from their growth arrest and restarted the nucleic acid synthesis and proliferation. Our study thus showed that GAS5 acts as a molecular switch for regulating quiescence and growth arrest in CD133+ population, that is responsible for aggressive biology of pancreatic tumors.