Κατεύθυνση Φαρμακευτική Χημεία
Library of the School of Science

2024-09-30

2024

Chatzipieris Filippos-Panteleimon

Αγγελική Κουρουνάκη, Καθηγήτρια, Τμήμα Φαρμακευτικής, ΕΚΠΑ (Επιβλέπουσα),
Τσοτίνης Ανδρέας, Καθηγητής Τμήμα Φαρμακευτικής, ΕΚΠΑ,
Πουλή Νικολαΐς, Καθηγήτρια Τμήμα Φαρμακευτικής, ΕΚΠΑ

Σύνθεση παραγώγου καρβαζολίου ως αναστολέα της συνθετάσης του σκουαλενίου: Ιn vivo αξιολόγηση σε πρότυπο μυός Μη Μικροκυτταρικού Καρκίνου του Πνεύμονα (NSCLC)

Greek

Synthesis of a carbazole derivative as an inhibitor of SQS: Ιn vivo evaluation in a mouse model of Non-Small Cell Lung Cancer (NSCLC)

Cholesterol is an important biomolecule for life and human health. When its biosynthetic mechanisms are dysregulated, the body is led to pathological conditions, such as cardiovascular disease neurodegeneration or cancer. Among others, cholesterol and its derivatives play a key role in carcinogenesis and metastasis. Therefore inhibition of excessive cholesterol biosynthesis could lead to the manifestation of anticancer and antimetastatic activity. Specifically, the enzyme Squalene Synthase (SQS), which catalyzes the first specialized step of cholesterol biosynthesis (the production of squalene from two molecules of farnesyl pyrophosphate), has been considered in recent years as a promising anticancer target, as its expression is shown to be increased in many types of cancer. In addition, increased expression of SQS has been suggested as a potential biomarker in various cancers.

The purpose of this research work is to study a potent known inhibitor of squalene synthase (SQS), which previously showed promising antimetastatic and anticancer activity in vitro. The synthesis of 1-allyl-2-[3-(benzylamino)propoxy]carbazole was carried out and its pharmacological activity was evaluated in an in vivo C57BL/6 mouse model of non-small cell lung cancer (NSCLC). Regarding the synthesis of 1-allyl-2-[3-(benzylamino)propoxy]carbazole, a 4-step synthetic route with good overall yields (40 to 98%) was followed. In the 1st step, the 2-hydroxycarbazole carries out a nucleophilic attack on the allylic bromide mainly through an SN2 process. Thus, 2-allyloxycarbazole is formed, which via a Claisen rearrangement, provides 1-allyl-2-hydroxycarbazole. The latter reacts with 1,3-dibromopropane (via an SN2 process) to afford 1-allyl-2-(3-bromopropoxy)carbazole. Nucleophilic attack of benzylamine on 1-allyl-2-(3-bromopropoxy)carbazole (SN2 process) produces compound 1, the final product: 1-allyl-2-[3-(benzylamino)propoxy]carbazole. Compound 1 was administered to a C57BL/6 mouse model with NSCLC and its effect was evaluated after a period of 20 days. Mice received 15 mg / kg animal weight of compound 1 twice daily. At the endpoint of the experiment, lungs and bronchoalveolar lavage fluid (BALF) were collected. Based on the results, it appears that administration of compound 1 reduces cancer-induced inflammation in the groups that received it, showing anti-inflammatory activity.

Further, three lung lobes (superior, inferior and post-caval lobes) were used for histology experiments; superficial and deep sections were taken from each lung sample for Hematoxylin – Eosin (H&E) staining. The sections that were stained with H&E were photographed and pictures were analysed and statistically processed. The results showed that the administration of compound 1 leads to a reduction in cancer when it is administered before the cancer has time to establish itself in the tissue and metastasize, i.e. in its initial stages.

Science

Health Sciences

carbazole derivative, squalene synthase (SQS) inhibitors, non-small cell lung cancer (NSCLC), cholesterol, C57BL/6 mice.

Yes

5

Yes

45

82

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https://pergamos.lib.uoa.gr/uoa/dl/object/3417827