Design of Fluorescent ALDH1A1 Targeting Compounds: Theranostic Agents Against Cancer Stem Cells

Majee, Aniket (2022) Design of Fluorescent ALDH1A1 Targeting Compounds: Theranostic Agents Against Cancer Stem Cells. Masters thesis, Indian Institute of Science Education and Research Kolkata.

Text (MS dissertation of Aniket Majee (17MS187)) 17MS187_Thesis_file.pdf - Submitted Version Restricted to Repository staff only Download (7MB)

Abstract

The main line of thought for this project emerges from the fact that to be able to selectively inhibit and detect ALDH1A1 would provide further details on their roles in cancer proliferation and probably even open new directions in cancer diagnostics. Previously in the lab a BODIPYderivative, 10-(chloromethyl)-5,5-difluoro-1,3,7,9-tetramethyl-5H-4λ⁴,5λ⁴-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine (named as ‘BODIPY-CH2Cl’) was synthesized which is esteemed as another choice to develop such probes. Aside from that, some other fluorophores like naphthalimide derivatives were also available. Linking such fluorophores with an ALDH1A1 selective isatin derivative could provide probes that could be potent against ALDHhigh CSCs or help detect such cell population. The objective of this project was to design an ALDH1A1 isoform-selective fluorescent probe by joining a suitable fluorophore with a known ALDH1A1 inhibitor. Indoline-2,3-dione (or isatin) was chosen as the inhibitor part of the probe for this project due to its known specificity. Throughout this project, two different fluorophores, namely BODIPY and naphthalimide derivatives, were used to link with the inhibitor part. Reactions were performed to connect compounds A4 and A5 (isatin derivatives attached with the 3-bromopropylamine linker) with BODIPY-CH2Cl, but the products could not be isolated. In an alternative route, the free amine group of compounds A4 and A5 was converted to isocyanate, but they could not be isolated and stored due to their unstable nature. Amination reaction was performed on BODIPY-CH₂Cl, but a primary and secondary amine mixture was obtained. In this case, the BODIPY derivative could not be attached to the isatin moiety; so, the potential of the target compound as an ALDH1A1 specific probe remains unexplored. Isatin was attached with the naphthalimide derivative B4 through a substitution reaction. The compound was characterized by ¹H NMR; ¹³C and HMQC NMR and HRMS experiments were to be performed. Target compound B8 was found to be less fluorescent than its parent compound B4. This fluorescence quenching could have been caused by photoinduced electron transfer (PET) or FRET mechanism, where the excited naphthalimide moiety could act as the donor and the isatin chromophore as the acceptor. Further experiments like UV-Vis and fluorescence spectroscopy need to be performed to get a better understanding of the photophysical properties of the compound. As observed for some of the naphthalimide derivatives, it is yet to be checked if this compound is eligible for two-photon fluorescence microscopy.

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