An Unusual Michael-Induced Skeletal Rearrangement of a Bicyclo[3.3.1]nonane Framework of Phloroglucinols to a Novel Bioactive Bicyclo[3.3.0]octane

A novel skeletal rearrangement of bicyclo[3.3.1]nonane-2,4,9-trione (16) to an unprecedented highly functionalized bicyclo[3.3.0]octane system (17), induced by an intramolecular Michael addition, is presented. This novel framework was found to be similarly active to hyperforin (1), against PC-3 cell lines. A mechanistic study was examined in detail, proposing a number of cascade transformations. Also, reactivity of the Δ7,10-double bond was examined under several conditions to explain the above results

Design, synthetic approaches and total synthesis of a New TREN-type FLuorescent Zinc Probe

Στην παρούσα διατριβή περιγράφεται ο σχεδιασμός, οι συνθετικές προσεγγίσεις και η ολική σύνθεση ενός φθορίζοντα δείκτη ψευδαργύρου. Η συγκεκριμένη ένωση αποτελεί παράγωγο της 7-αμινο-4-μεθυλοκουμαρίνης και του συμπλοκοποιητή ψευδαργύρου TREN. Η επιλογή του χρωμοφόρου έγινε με βάση τα φθορισμομετρικα χαρακτηριστικά του συγκεκριμένου παραγώγου της κουμαρίνης και τους αντίστοιχους περιορισμούς που επιβάλλουν η φύση των προς μελέτη υποστρωμάτων και η διαθέσιμη οργανολογία. Η επιλογή του χειλικού μέρους της ένωσης έγινε λαμβάνοντας υπόψη παράγοντες όπως η συγγένεια του προς το ιόν και η εκλεκτικότητά του σε σχέση με άλλα μέταλλα. Εκτός από τη σύνθεση του φθορίζοντα δείκτη ψευδαργύρου, η παρούσα εργασία περιλαμβάνει προκαταρκτικές μελέτες του μηχανισμού της δημιουργίας Ν,Ν-διυποκατεστημένων φορμικών 2-αμινοαιθυλο εστέρων κατά την κατεργασία Ν,Ν διυποκατεστημένων 2-βρωμοαίθυλο- αμινών με DMF, την διατύπωση μίας πρώτης υπόθεσης για τον μηχανισμό αυτό και προτάσεις για μελλοντικές μελέτες που πιθανόν να οδηγήσουν στην αποσαφήνιση του μηχανισμού.The major goal of this thesis was the design, the synthetic approaches, and the total synthesis of a coumarin-type fluorescent Zn2+ probe. The structure of the probe is comprised of a fluorophore namely, 2-amino-4-methylcoumarin connected to TREN, a known selective Zn2+ chelator. The choice of the chromophore was based on the fluorescence spectral profile of the coumarin analog, as well as on the respective restrictions posed by the type of the desired zinc-probe applications and the necessary instrumentation. The chelator was selected on the basis of its affinity to zinc ions and its selectivity to Zn2+ versus other ions present in the systems of study. This thesis also includes a set of preliminary experiments aiming at the study of the formation of N,N-disubsituted 2-aminoethyl formates during the reaction of N,N-disubstituted 2-bromoethylamines with DMF in the presence of DIPEA. A tentative reaction mechanism is proposed as well as a number of substrates to be studied in order to ascertain the detailed mechanism of the reaction

A Theranostic Small-Molecule Prodrug Conjugate for Neuroendocrine Prostate Cancer

After androgen deprivation therapy, a significant number of prostate cancer cases progress with a therapy-resistant neuroendocrine phenotype (NEPC). This represents a challenge for diagnosis and treatment. Based on our previously reported design of theranostic small-molecule prodrug conjugates (T-SMPDCs), herein we report a T-SMPDC tailored for targeted positron emission tomography (PET) imaging and chemotherapy of NEPC. The T-SMPDC is built upon a triazine core (TZ) to present three functionalities: (1) a chelating moiety (DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) for PET imaging when labeled with 68Ga (t1/2 = 68 min) or other relevant radiometals; (2) an octreotide (Octr) that targets the somatostatin receptor 2 (SSTR2), which is overexpressed in the innervated tumor microenvironment (TME); and (3) fingolimod, FTY720—an antagonist of sphingosine kinase 1 that is an intracellular enzyme upregulated in NEPC. Polyethylene glycol (PEG) chains were incorporated via conventional conjugation methods or a click chemistry reaction forming a 1,4-disubstituted 1,2,3-triazole (Trz) linkage for the optimization of in vivo kinetics as necessary. The T-SMPDC, DOTA-PEG3-TZ(PEG4-Octr)-PEG2-Trz-PEG3-Val-Cit-pABOC-FTY720 (PEGn: PEG with n repeating ethyleneoxy units (n = 2, 3, or 4); Val: valine; Cit: citrulline; pABOC: p-amino-benzyloxycarbonyl), showed selective SSTR2 binding and mediated internalization of the molecule in SSTR2 high cells. Release of FTY720 was observed when the T-SMPDC was exposed to cathepsin B, and the released FTY720 exerted cytotoxicity in cells. In vivo PET imaging showed significantly higher accumulation (2.1 ± 0.3 %ID/g; p = 0.02) of [68Ga]Ga-DOTA-PEG3-TZ(PEG4-Octr)-PEG2-Trz-PEG3-Val-Cit-pABOC-FTY720 in SSTR2high prostate cancer xenografts than in the SSTR2low xenografts (1.5 ± 0.4 %ID/g) at 13 min post-injection (p.i.) with a rapid excretion through the kidneys. Taken together, these proof-of-concept results validate the design concept of the T-SMPDC, which may hold a great potential for targeted diagnosis and therapy of NEPC

An Unusual Michael-Induced Skeletal Rearrangement of a Bicyclo[3.3.1]nonane Framework of Phloroglucinols to a Novel Bioactive Bicyclo[3.3.0]octane

A novel skeletal rearrangement of bicyclo[3.3.1]nonane-2,4,9-trione (<b>16</b>) to an unprecedented highly functionalized bicyclo[3.3.0]octane system (<b>17</b>), induced by an intramolecular Michael addition, is presented. This novel framework was found to be similarly active to hyperforin (<b>1</b>), against PC-3 cell lines. A mechanistic study was examined in detail, proposing a number of cascade transformations. Also, reactivity of the Δ^7,10-double bond was examined under several conditions to explain the above results

Aminonaphthalene 2‑Cyanoacrylate (ANCA) Probes Fluorescently Discriminate between Amyloid‑β and Prion Plaques in Brain

A major challenge for diagnosing and monitoring the progression of amyloid-based diseases is the capability to distinguish between amyloid deposits that are associated with related, but distinctly different, diseases. Here, we demonstrate that aminonaphthalenyl 2-cyanoacrylate-based probes can fluorescently discriminate between different types of amyloid deposits in brain. The discriminating capability of these molecular rotors is due to the stabilization of the ground versus excited states of these probes as a function of the polarity of their microenvironment (i.e., within the binding pocket on the amyloid). This property makes it possible, for the first time, to estimate the inherent static relative permittivity (ε₀) of the binding pocket of each amyloid within tissue. The capability to selectively follow the deposition of specific amyloids in tissue may provide important information for therapeutic development that is not readily accessible from currently available technology

An Unusual Michael-Induced Skeletal Rearrangement of a Bicyclo[3.3.1]nonane Framework of Phloroglucinols to a Novel Bioactive Bicyclo[3.3.0]octane

A novel skeletal rearrangement of bicyclo[3.3.1]nonane-2,4,9-trione (<b>16</b>) to an unprecedented highly functionalized bicyclo[3.3.0]octane system (<b>17</b>), induced by an intramolecular Michael addition, is presented. This novel framework was found to be similarly active to hyperforin (<b>1</b>), against PC-3 cell lines. A mechanistic study was examined in detail, proposing a number of cascade transformations. Also, reactivity of the Δ^7,10-double bond was examined under several conditions to explain the above results