No abstract

The selective recognition and imaging of oncogene specific G-quadruplex (GQ) structures holds great promise in the development of diagnostic therapy (theranostics) for cancer and has been challenging due to their structural dynamics and diversity. We report selective recognition of GQ by a small molecule through unique hybrid loop stacking and groove binding mode with turn on far-red fluorescence response and anticancer activity demonstrating the potential implications for GQ-targeted cancer theranostics. Methods: Biophysical investigation reveal the turn on far-red emission property of TGP18 for selective recognition of GQ. In cellulo studies including DNA damage and oxidative stress evaluation guided us to perform in vitro (3D spheroid) and in vivo (xenograft mice model) anti-cancer activity, and tumor tissue imaging to assess the theranostic potential of TGP18. Results: Neocuproine-based far-red turn on fluorescence probe TGP18 shows GQ-to-duplex selectivity and specifically recognizes BCL-2 GQ with high affinity through a unique hybrid binding mode involving loop-stacking and groove interactions. Our study reveals that the selective recognition originating from the distinct loop structure of GQ that alters the overall probe interaction and binding affinity. TGP18 binding to anti-apoptotic BCL-2 GQ ablates the pro-survival function and elicit anti-cancer activity by inducing apoptosis in cancer cells. We deciphered that inhibition of BCL-2 transcription synergized with signaling cascade of nucleolar stress, DNA damage and oxidative stress in triggering apoptosis signaling pathway. Conclusion: Intervention of GQ mediated lethality by TGP18 has translated into anti-cancer activity in both in vitro 3D spheroid culture and in vivo xenograft models of lung and breast cancer with superior efficacy for the former. In vivo therapeutic efficacy supplemented with tumor 3D spheroid and tissue imaging potential define the role of TGP18 in GQ-targeted cancer theranostics.

The ability of mitochondrial DNA (mtDNA) to form G‐quadruplex (GQ) structures suggest their role in diseases involving mitochondrial dysfunction. Detection and visualization of GQ structures specific to mitochondria using fluorescent probes aid in monitoring mtDNA dynamics and homeostasis. Herein, we report the first study of flavylium‐methine rotor probes (FLV1 and FLV3) for discrimination of GQ and non‐GQ structures through turn‐on near infrared (NIR) fluorescence response. The target‐induced disaggregation (TID) and restricted intramolecular rotation (RIR) of FLV1 in the presence of GQ specific to VEGF oncogene leading to significant fluorescence enhancement and delayed lifetime. The colocalization studies with different organelle trackers confirmed selective localization of FLV1 in mitochondria. Nuclease digestion assays showed mitochondria‐specific accumulation of the probe is independent of membrane potential and selectively bind mtDNA GQ. Our study demonstrates the biocompatible and photostable flavylium‐methine dyes as a new category of probes to selectively label mitochondria and target mtDNA GQ in live and fixed cells.

Bowl shaped molecules are useful for making molecular capsules with suitable non-covalent bonds. We appended cyclotriguaiacylene with biologically important adenine and thymine to make capsule in solution by hydrogen bonding.