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Properties of Benzoquinazolines

#A-649


Benzo[h]quinazolines: Chemical and Enzymatic Synthesis and Study

Tech Area / Field

  • CHE-SYN/Basic and Synthetic Chemistry/Chemistry
  • BIO-CHM/Biochemistry/Biotechnology

Status
8 Project completed

Registration date
04.12.2000

Completion date
22.01.2007

Senior Project Manager
Osipov E A

Leading Institute
Institute of Fine Organic Chemistry, Armenia, Yerevan

Supporting institutes

  • Institute of Microbiology, Armenia, Abovian

Collaborators

  • University of Maryland at Baltimore / Biotechnology Institute, USA, MD, Baltimore\nUniversity of Missouri, USA, MO, St Louis

Project summary

The Project concerns the chemical and enzymatic synthesis and study of new derivatives of benzo[h]quinazolines with high functional activities.

Benzo[h]quinazolines are poorly studied systems. Number of publications related to synthesis and investigations of chemical and biological properties of benzo[h]quinazolines is strictly limited because of the absence of accessible and common methods of synthesis of such compounds. Despite of small number of publications in this area, it has been shown that the synthesized benzo[h]quinazolines displayed valuable biological properties, such as adrenomimetic, antitumor, antihypertensive, antimicrobial, antibacterial, antimalarial, antidepressive, anesthetic, and antiphlogistic activities. Therefore the actuality of investigations in this area is evident.

During the last 15 years at the Institute of Fine Organic Chemistry of the NAS of Armenia (IFOC) the large experimental work on synthesis and study of spirocyclic and spiroheterocyclic compounds with wide spectrum of biological activities has been carried out.

The complex of preliminary works has been developed on the elaboration of efficient methods for the synthesis of spirocyclic benzoquinazolines, which in the fifth position are spiroconnected with cycloalkanes. The majority of synthesized compounds have displayed strong psychotropic and antitumor properties.

Some of the methods for the synthesis of spirocyclic benzo[h]quinazolines are developed at the IFOC for the first time. The results obtained have shown that the development of the new more suitable approaches for the synthesis of benzo[h]quinazolines and the complex study of their chemical, biological and quantum-chemical properties have an obvious significance.

It is worthy to notice that till now there are no data on the enzymatic synthesis of benzoquinazolines. The solution of the task is an important step not only for the chemistry of benzo[h]quinazolines but also for the biocatalytic synthesis of other fine chemicals. The free and immobilized forms of specific enzymes produced by extremophilic and hyperextremophilic microorganisms will be applied for this purpose.

The Institute of Microbiology of the National Academy of Sciences of Armenia (INMIA) has been for more than 20 years engaged in the study of enzymatic properties of different groups of microorganisms and their application for the production of various physiologically active compounds.

Based on a vast and well studied Culture Collection and Database including more than 2000 extremophilic forms, several producers of useful enzymes as cyclomaltodextrin glucanotransferases, inulinases, amylases, galactosidases, lipases, aspartases, aspartate-b-decarboxylases, fumarases, proteases, etc., have been identified. The enzymes have been isolated and comparatively studied. The results obtained have shown significant differences in enzymatic patterns of biocatalysts isolated from various species of microorganisms. It has been revealed that each enzyme possesses unique properties, which may be similar within the species range of the producers.

The Institutes were involved in R&D for military purposes in the Former SU and weapon scientists are engaged within the Project. Actually the Project represents the conversion of military R&D to civil needs.

On different stages of the Project some other institutions will be involved.

The Project represents an integrated complex of chemical, quantum-chemical, microbiological, biochemical, biotechnological, biological and physico-chemical studies with application of modern technologies.

The main purpose of chemical researches is the development of efficient and preparative approaches for the synthesis of spirocyclic benzo[h]quinazolines. For this purpose it was planned to carry out the accessible methods for the synthesis of convenient key compounds – b-aminoesteres and b-aminonitriles of dihydronaphthalenes series substituted with alkyl-, dialkyl- and/or cycloalkyl groups as well as spirocyclic fragments in the hydrogenated ring. The obtained aminoesters and aminonitriles will serve as substrates for the synthesis of di-, tetra- and hexahydrobenzo[h]quinazolines with different substitutes or spirocyclic fragment in the fifth position. Due to a number of transformation reactions of functionalized benzo[h]quinazolines the passage to more complicated heterocyclic and spiroheterocyclic systems will be realized. Methods for the synthesis of benzo[h]quinazolines comprising different carbohydrates, including their cyclic forms is planned to develop.

The quantum-chemical researches aimed to explain and to justify the experimental data outgoing from the basis of geometry, charges on atoms, density of population on molecular orbital, p-orbital density on HOMO/LUMO, heat formation, dipole moments and other characteristics. The data obtained will be used for the detection of control type in ring formation reaction (thermodynamic or kinetic). In this purpose the modern software packages will be used (Hyperchem, Gaussian), permitting to do calculations both at a semi-empirical, and on not empirical levels. It is planned to use the results of calculations for forecasting of selectivity of different nucleophilic substitution reactions. The study and realization of a conformation analysis of spiroheterocyclic compounds will allow to reveal the percent weight of each conformer in equilibrium, and also the reactivity of everyone at different reactions. One of the main purposes of calculations is the finding of the relation of definite biological properties from quantum-chemical characteristics both of separate functional groups and all molecules as a whole.

The biological researches will be conducted in the appropriate laboratories of IFOC. The main purpose of planned researches is the detection of compounds with antidepressive and antitumor properties.

The main purpose of physico-chemical researches is the identification of the synthesized compounds by modern physico-chemical methods.

Microbiological researches aimed to obtain and to characterize efficient extremophilic producers of needed enzymes, to develop growth conditions and biosynthetic pathways for enzymes overproduction.

The main goals of biochemical investigations have to be the study of physico-chemical and biochemical properties of enzymes produced by extremophilic and hyperextremophilic microorganisms.

Biotechnological R&D includes the development of process-engineering for the production of new functional compounds of high commercial value. The samples of the products have to be obtained in pilot-scale conditions.

The results expected of the Project have the scientific, practical and economical significances, as the development of benzoquinazolines chemistry, biochemistry of extremophilic and hyperextremophilic microorganisms as well as methods for the realization of enzymatic transformations in organic and low-water media. The Project realization permits to carry out the efficient methods for the synthesis of high-value derivatives of benzoquinazolines.

The realization of the Project providing former weapons scientists of IFCO and INMIA opportunities to redirect their talents to peaceful activities, in particularly for the chemical and enzymatic synthesis and study of poorly studied heterocyclic systems – benzo[h]quinazolines.

The Project is open for international community: joint investigations, synthesis of biologically active benzoquinazolines and results discussion.

In the framework of Project Proposal the role of foreign collaborators is as follows:

– provide each other the new specific benzoquinazoline derivatives for their investigation and references;


– shared use of test samples and certain equipment for the characterization of compounds obtained;
– information exchange in the course of project implementation;
– specialist exchange;
– participation in joint seminars.


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