Design and Development of Novel Targeted Anticancer Drugs

Akpughe, Ewoma

Abstract

Despite major advances in treatments for cancer, the delivery of small molecule chemotherapeutics to tumour cells selectively and the circumvention of multidrug resistance persist as obstacles that limit their efficacy in the clinical setting. One approach to improve the selective targeting of anticancer agents is their conjugation to essential vitamins. The sodium multivitamin transporter (SMVT) is overexpressed in many cancer cells and translocate biotin.

In this research, two series of novel biotin-aminoanthraquinone conjugates were synthesised and characterised by high-resolution mass spectrometry and NMR spectroscopic methods. Members of these series were designed to incorporate the dual features of a biotin ligand for recognition by SMVT and a lysosomotropic pharmacophore to promote targeted delivery to the lysosomes of cancer cells by exploiting differences to normal cells for lysosomal accumulation and disruption, leading to cell death. First-generation (Series 1) compounds had 1,5-diamino-AQ chromophores, whereas second-generation (Series 2) had 1-amino-4-hydroxy-AQ chromophores.

First-generation conjugates, EA13 and EA14, and unconjugated analogues EA16(II) and EA19, exhibited potent anti-proliferative activity (IC50 values in the low micromolar range) against the SMVT-expressing MCF-7 breast carcinoma cell line. Confocal microscopy studies showed that none of the Series 1 compounds localised within the lysosomes. The involvement of the SMVT protein in their mechanism of action was not established. Second-generation (Series 2) biotin conjugates, EA23, EA35 and EA39, were potently anti-proliferative against MCF7 and accumulated strongly in the lysosomes, a pattern shared by EA22, the unconjugated precursor to EA23.

Lysosomal-targeting lead compounds retained strong anti-proliferative activity in the HCT-15 colon carcinoma cell line, which has high P-glycoprotein expression, suggesting they may have the potential to circumvent a major mechanism of drug resistance. Key biotin-aminoanthraquinone conjugates have been shown to accumulate in the lysosomes of both MCF-7 and HCT-15 cancer cells, avoiding other organelles and the nucleus, may have the potential for the design of new drugs with improved therapeutic index and less systemic side effects.

• Thesis Type: Thesis
• Deposit Date: Aug 18, 2023
• Publicly Available Date: Aug 18, 2023
• DOI: https://doi.org/10.17869/enu.2023.3170294
• Award Date: Jul 5, 2023