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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 301: 122955, 2023 Nov 15.
Article in English | MEDLINE | ID: mdl-37301032

ABSTRACT

Herein we report an easy, rapid and cost-effective method for spectroscopic sensing of a prostate cancer biomarker prostate specific antigen (PSA) using a novel nanocomposite. The material is a synthetic quinoxaline derivative-based iron nanocomposite fabricated on graphene nanoplatelet surface (1d-Fe-Gr). Presence of graphene enhanced the efficacy of synthesized 1d-Fe-Gr to sense PSA in serum medium with an impressive limit of detection (LOD) value of 0.878 pg/mL compared to 1d-Fe alone (LOD 17.619 pg/mL) using UV-visible absorption spectroscopy. LOD of PSA by 1d-Fe-Gr using Raman spectroscopy is even more impressive (0.410 pg/mL). Moreover, presence of interfering biomolecules like glucose, cholesterol, bilirubin and insulin in serum improves the detection threshold significantly in presence of 1d-Fe-Gr which otherwise cause LOD values of PSA to elevate in control sets. In presence of these biomolecules, the LOD values improve significantly as compared to healthy conditions in the range 0.623-3.499 pg/mL. Thus, this proposed detection method could also be applied efficiently to the patients suffering from different pathophysiological disorders. These biomolecules may also be added externally during analyses to improve the sensing ability. Fluorescence, Raman and circular dichroism spectroscopy were used to study the underlying mechanism of PSA sensing by 1d-Fe-Gr. Molecular docking studies confirm the selective interaction of 1d-Fe-Gr with PSA over other cancer biomarkers.


Subject(s)
Graphite , Nanocomposites , Male , Humans , Prostate-Specific Antigen , Iron , Graphite/chemistry , Molecular Docking Simulation , Biomarkers, Tumor , Nanocomposites/chemistry
2.
ACS Omega ; 7(8): 6488-6501, 2022 Mar 01.
Article in English | MEDLINE | ID: mdl-35252645

ABSTRACT

The elevated level of endogenous oxidative DNA damage and spontaneous deamination of DNA bases in cancer cells substantially increase the abasic sites in DNA via base excision repairs (BERs). Thus, the predominant BER pathway is a favorable target for cancer therapy. Interestingly, elevated levels of glutathione (GSH) in certain cancer cells, such as colon cancer, are associated with acquired resistance to several chemotherapeutic agents, which increase the difficulty for the treatment of cancer. Here, we have reported an ideal nitro group-containing monoquinoxaline DNA intercalator (1d), which is reduced into a fluorescent quinoxaline amine (1e) in the presence of GSH; concurrently, 1e (∼100 nM concentration) selectively causes the in vitro cleavage of abasic sites in DNA. 1e also binds to the tetrahydrofuran analogue of the abasic site in the nanomolar to low micromolar range depending on the nucleotide sequence opposite to the abasic site and also induces a structural change in abasic DNA. Furthermore, the amine compound (1e) augments the response of the specific bifunctional alkylating drug chlorambucil at a much lower concentration in the human colorectal carcinoma cell (HCT-116), and their combination shows a potential strategy for targeted therapy. Alone or in combination, 1d and 1e lead to a cascade of cellular events such as induction of DNA double-stranded breaks and cell arrest at G0/G1 and G2/M phases, eventually leading to apoptotic cell death in HCT-116 cells. Hence, the outcome of this study provides a definitive approach that will help optimize the therapeutic applications for targeting the abasic site in cancer cells.

3.
Eur J Med Chem ; 229: 113995, 2022 Feb 05.
Article in English | MEDLINE | ID: mdl-34802835

ABSTRACT

Cooperative disruption of Watson-Crick hydrogen bonds, as well as base-destacking, is shown to be triggered by a quinoxaline-based small molecule consisting of an N,N-dimethylaminopropyl tether, and a para-substituted benzyl moiety. This events lead to superstructure formation and DNA condensation as evident from biophysical experiments and classical molecular dynamics simulations. The DNA superstructure formation by mono-quinoxaline derivatives is highly entropically favored and predominantly driven by hydrophobic interactions. Furthermore, oversupercoiling of DNA and base-destacking cumulatively induces histone eviction from in-vitro assembled nucleosomes at lower micromolar concentrations implicating biological relevance. The DNA structural modulation and histone eviction capacity of the benzyl para-substituents are in the order: -I > -CF3> -Br > -Me > -OMe > -OH, which is largely guided by the polarity of benzyl para-substituent and the resulting molecular topology. The most hydrophobic derivative 3c with para-iodo benzyl moiety causes maximal disruption of base pairing and generation of superstructures. Both these events gradually diminish as the polarity of the benzyl para-substituent increases. On the other hand, quinoxaline derivatives having heterocyclic ring instead of benzyl ring, or in the absence of N,N-dimethylamino head-group, is incapable of inducing any DNA structural change and histone eviction. Further, the quinoxaline compounds displayed potent anticancer activities against different cancer cell lines which directly correlates with the hydrophobic effects of the benzyl para-substituents. Overall, the present study provides new insights into the mechanistic approach of DNA structural modulation driven histone eviction guided by the hydrophobicity of synthesized compounds leading to cellular cytotoxicity towards cancer cells.


Subject(s)
DNA/chemistry , Histones/metabolism , Quinoxalines/chemistry , Cell Line , Cell Survival/drug effects , DNA/metabolism , DNA Damage/drug effects , Drug Design , Humans , Hydrogen Bonding , Molecular Conformation , Quantum Theory , Quinoxalines/metabolism , Quinoxalines/pharmacology , Thermodynamics
4.
Chembiochem ; 22(2): 359-363, 2021 01 15.
Article in English | MEDLINE | ID: mdl-32869357

ABSTRACT

Transfer RNAs (tRNAs) are fundamental molecules in cellular translation. In this study we have highlighted a fluorescence-based perceptive approach for tRNAs by using a quinoxaline small molecule. We have synthesised a water-soluble fluorescent pyrimido-quinoxaline-fused heterocycle containing a mandatory piperazine tail (DS1) with a large Stokes shift (∼160 nm). The interaction between DS1 and tRNA results in significant fluorescence enhancement of the molecule with Kd ∼5 µM and multiple binding sites. Our work reveals that the DS1 binding site overlaps with the specific Mg2+ ion binding site in the D loop of tRNA. As a proof-of-concept, the molecule inhibited Pb2+ -induced cleavage of yeast tRNAPhe in the D loop. In competitive binding assays, the fluorescence of DS1-tRNA complex is quenched by a known tRNA-binder, tobramycin. This indicates the displacement of DS1 and, indeed, a substantiation of specific binding at the site of tertiary interaction in the central region of tRNA. The ability of compound DS1 to bind tRNA with a higher affinity compared to DNA and single-stranded RNA offers a promising approach to developing tRNA-based biomarker diagnostics in the future.


Subject(s)
Heterocyclic Compounds/chemistry , Magnesium/chemistry , Pyrimidines/chemistry , Quinoxalines/chemistry , RNA, Transfer/chemistry , Binding Sites , Molecular Structure
5.
Chem Commun (Camb) ; 55(93): 14027-14030, 2019 Nov 19.
Article in English | MEDLINE | ID: mdl-31690898

ABSTRACT

RNA-biased small molecules with a monoquinoxaline core target the L-shaped structure of subdomain IIa of Hepatitis C virus internal ribosome entry site (IRES) RNA in proximity to the Mg2+ binding site. The binding event leads to the destacking of RNA bases, resulting in the inhibition of IRES-mediated translation and HCV RNA replication.


Subject(s)
Antiviral Agents/pharmacology , Hepacivirus/drug effects , Internal Ribosome Entry Sites/drug effects , Quinoxalines/pharmacology , RNA, Viral/drug effects , Antiviral Agents/chemistry , Hepacivirus/genetics , Humans , Internal Ribosome Entry Sites/genetics , Molecular Conformation , Quinoxalines/chemistry , RNA, Viral/genetics , Virus Replication/drug effects
6.
Biochemistry ; 57(38): 5557-5563, 2018 09 25.
Article in English | MEDLINE | ID: mdl-30169956

ABSTRACT

Small molecules that intercalate DNA have tremendous therapeutic potential. Typically, DNA intercalators do not alter the overall DNA double-helical structure, except locally at the intercalation sites. In a previous report, we showed that a quinoxaline-based intercalator with a mandatory benzyl substitution (1d) induced an unusually large circular dichroism signal upon DNA binding, suggesting the formation of intercalated DNA superstructures. However, no detailed structural studies have been reported. Using atomic force microscopy, we have probed the nature of the superstructure and report the formation of a plectonemically oversupercoiled structure of pBR322 plasmid DNA by 1d, where close association of distant DNA double-helical stretches is the predominant motif. Without the benzyl moiety (1a), no such DNA superstructure was observed. Similar superstructures were also observed with doxorubicin (dox), a therapeutically important DNA intercalator, suggesting that the superstructure is common to some intercalators. The superstructure formation, for both intercalators, was observed to be GC-specific. Interestingly, at higher concentrations (1d and dox), the DNA superstructure led to DNA condensation, a phenomenon typically associated with polyamines but not intercalators. The superstructure may have important biological relevance in connection to a recent study in which dox was shown to evict histone at micromolar concentrations.


Subject(s)
Antibiotics, Antineoplastic/chemistry , DNA/chemistry , Doxorubicin/chemistry , Intercalating Agents/chemistry , Nucleosomes , Plasmids/chemistry , Quinoxalines/chemistry , DNA Replication , Humans , Microscopy, Atomic Force , Models, Molecular , Molecular Structure , Nucleic Acid Conformation
7.
Chembiochem ; 2018 Jun 13.
Article in English | MEDLINE | ID: mdl-29897151

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD), which is characterized by excess accumulation of triglyceride in hepatocytes, is the major cause of chronic liver disease worldwide and no approved drug is available. The mechanistic target of rapamycin (mTOR) complexes has been implicated in promoting lipogenesis and fat accumulation in the liver, and thus, serve as attractive drug targets. The generation of non- or low cytotoxic mTOR inhibitors is required because existing cytotoxic mTOR inhibitors are not useful for NAFLD therapy. New compounds based on the privileged adenosine triphosphate (ATP) site binder quinoline scaffold conjugated to glucose and galactosamine derivatives, which have significantly low cytotoxicity, but strong mTORC1 inhibitory activity at low micromolar concentrations, have been synthesized. These compounds also effectively inhibit the rate of lipogenesis and lipid accumulation in cultured hepatocytes. This is the first report of glycomimetic-quinoline derivatives that reduce lipid load in hepatocytes.

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