Synthesis and Preclinical Development of novel Organoselenium compounds as Multi-Target and Bioactive Agents

Abstract

The aim of the present Ph.D. thesis entitled "Synthesis and preclinical development of novel organoselenium compounds as multi-target and bioactive agents" is the development of new active Se-containing molecules and, in this way, to expand the knowledge on the design and molecular biology of organoselenium derivatives mainly in the field of cancer treatment and prevention. The results obtained during the experimental work are divided into four thematic blocks (Part I, II, III, and IV), and comprise one hundred and twelve novel Se-containing derivatives starting from the design, synthesis, purification, and structural characterization to their preliminary evaluation as theraputic agents. All the compounds have been assessed as anticancer molecules, but certain compounds have been also evaluated as acetylcholinestare (AChE) inhibitors in the field of Alzheimer's disease (AD). Part I, entitled "Natural and synthetic allylic derivatives", includes Chapter 1 which contains a literature review with future perspectives on the allyl moiety, which is present in a great variety of natural sources, and its role in the design of novel anticancer drugs. Based on Chapter 1, different series of molecules, combining Se with the allylic entity (among other entities), have been designed as future anticancer agents and are collected in the following parts. Parts II, III, and IV are divided according to the functional group in which Se is found in the molecule. Thus, Part II collects selenoesters (Chapters 2-5), Part III includes acylselenoureas (Chapter 6), and Part IV contains 1,2,4-diselenazolidines (Chapter 7). Part II is further divided into 3 sections: Part II.1, Part II.2, and Part II.3. Part II.1 is entitled "First Generation", since it presents the first approach in the development of allylic selenolester derivatives (Chapters 2 and 3). In Chapter 2, the preliminary anticancer activity and the inhibition of AChE are studied. Then, Chapter 3 presents the evaluation as cancer-associated carbonic anhydrase (CA) isoforms IX and XII inhibitors. Part II.2 comprises the "Second Generation" of allylic selenolester derivatives and the molecules developed therein are symmetrical with two-substituted selenolester functionalities such as their sulfur analogs, the allyl disulfides, present in garlic (Chapter 4). Besides, their biological evaluation as potent chemotherapeutic agents is reported. Finally, Part II.3 includes molecules that in addition to having a functional selenoester group also have a benzo[c][1,2,5]selenadiazole moiety and it also reports their preliminary cytotoxic activity (Chapter 5). Part III presents the acylslenourea derivatives containing the allyl, propargyl, or propyl chain. These derivatives have been evaluated as dual radical scavenging and anticancer agents (Chapter 6). Part IV includes a series of 1,2,4-diselenazolidines that were formed as by-products during the synthesis of acylselenoureas. This is a very novel Se-structure that has not been evaluated as a chemotherapeutic agent to date (Chapter 7).