Thesis title: Rational design and synthesis of organic compounds: from natural prenylated xanthones to fluorescent BODIPY probes
PART A. RATIONAL DESIGN AND SYNTHESIS OF A NOVEL BODIPY‑BASED FLUORESCENT PROBE SELECTIVE FOR TAU TANGLES. Since no specific therapies to treat Alzheimer's disease exist yet, the scientific research focused on the study of accurate and specific diagnostic methods. Numerous studies have shown a strong correlation between the number of NFTs of tau protein and Alzheimer's disease progression, making the quantitative detection of tau very promising from a clinical point of view. Thanks to crystallographic structures elucidation by Cryo-EM of the hexapeptide fragment PHF6, responsible for the propensity of the p-tau protein itself to assemble into fibrils, and to construction of a 6-mer of the most conserved channel, the interaction with several class of fluorophores has been studied by molecular docking. The BODIPY core emerged as privileged scaffold in the design of fluorescent probes owning to their relative ease of substitution and generally highly fluorescent nature. Based on these, a small-size focused library of BODIPY probes, BT1-8, has been rationally designed by extending the conjugation of position 3 of the BODIPY core with a highly conjugated systems ending with an aliphatic amine with a length in the range 13-19 Å and has been docked toward the 6-mer model. Among all, BT1 compound has been selected as the most promising selective p-tau probe in terms of in silico theoretical affinity, binding mode, and polarity, so an efficient, versatile, and cost-effective two-step synthetic strategy was developed. The probe has been tested in vitro onto human iPSC-derived NGN2-induced neuronal cell cultures and has shown excellent photophysical properties and high selectivity allowing in vitro imaging of hyperphosphorylated tau protein filaments with minimal background noise, confirming in silico studies. Synthetic organic chemistry and computational modelling, biochemistry and biology were all combined in a concerted multidisciplinary strategy to develop fluorescent sensors for boosting NFTs detection in patients through retinal spectral scans.
PART B. STUDIES TOWARD TOTAL SYNTHESIS OF A NATURAL XANTHONE, α-MANGOSTIN, BY ALUMINA-MEDIATED ORTHO-SELECTIVE PRENYLATION OF PHENOLS. The importance of natural occurring prenylated phenols, a type of important bioactive compounds presenting with prenyl group on the phenolic skeleton, has always been know. To date, about 371 structures with phenols or phenol ethers have been approved by FDA, and 55 of them are part of the WHO model list of essential medicines. α-Mangostin is the first and most abundant polyphenolics xanthone isolated from pericarps, bark, and dried sap of the mangosteen fruit (Garcinia mangostana L.), “superfruit” rich in prenylated and oxygenated xanthone derivatives widely used in traditional medicine in southeast Asia. A lot of groups have researched on its activities, which include antioxidant, anti-inflammatory, antibacterial and antitumor. In recent years, it has been found to exhibit the potential to slow down cognitive decline and to delay Alzheimer's disease. To date, the synthetic approaches for the total synthesis of α-Mangostin present in literature are only two. The first one, reported by Xu, D. et al., Natural Product Comm., 2013, 8 (8), consists of 8 steps with an overall yield of 8.3%, with the introduction of the prenyl side chains via aliphatic Claisen rearrangement and Wittig reaction. The second one, reported by Iikubo, K. et al., Tetrahedron Lett., 2002, 43 (2), provides the construction of two fragments (8 steps for each) and their respective coupling in PPh3-CCl4 conditions, to give α-Mangostin with an overall yield of 10% for 20 steps in total. The formal synthesis proposed here, provides the construction of the xanthone core in one step, with the use of Eaton’s reagent, and the introduction of the prenyl chains in one step, utilizing an alumina-mediated ortho-selective prenylation strategy developed by the Magolan lab at McMaster University, saving 8 steps in total. This chapter will focus on the synthetic strategies towards α-Mangostin, and the difficulties encountered throughout the synthesis including the alumina-mediated prenylation.