New reagents for organic synthesis of substances with high biological activity
Name of the project
A new type of reactivity of unsaturated nitro compounds as a synthetic platform for the production of new heterocyclic systems.
Head of the project and main contributors:
Head of the project: Aksenov Alexander Viktorovich – Head of Chair of Chemistry, Doctor of Chemical Science, Professor
Contributors: Aksenov N.A., Aksenov D.A., Alexandrova E.V., Aksenova I.V., Rubin M.A.
Project realization support mechanisms:
The project was supported by the Russian Science Foundation as part of the 2018 competition “Conducting fundamental research and exploratory research by individual research groups” (project number: 18-13-00238)
University subdivisions and industrial partners involved in the project:
Chair of Chemistry, the Institute of Mathematics and Natural Sciences
The project is based on solving the fundamental problem of searching for new reagents for organic synthesis and creating new synthetic methods, as well as identifying compounds with high biological activity among the synthesized substances. An approach developed by the scientific team based on the use of “smart” reaction media to obtain compounds related to the indole type alkaloids was used during realization of the project. The development of synthetic approaches to analogues of alkaloids containing an indolyl fragment is one of the central topics in modern organic and medical chemistry.
Developing studies of the antitumor activity of 2-aryl-2- (3-indolyl) acetohydroxamic acids, which demonstrated significant activity against glioma, melanoma, esophageal cancer and many other cancer cell lines, the team has faced the need to develop new approaches to analogical compounds that were not available in traditional ways. These analogues include hydroxamic acids themselves as well as some cyclic derivatives. These include 4'H-spiro [indole-3,5'-isoxazoles], which are not only structurally similar to hydroxamic acids, but also are analogical to natural compounds, which makes them interesting from the point of view of biological activity.
Current project results
- The mechanism of this transformation is deduced, optimization is carried out.
- Two approaches have been developed for the synthesis of 2- (3-oxoindol-2-yl) acetonitriles: the first one involves hexone base-catalyzed rearrangement of 4'H-spiro [indole-3,5'-isoxazoles], and the second direct method involves acid-catalyzed spirocyclization of indoles with nitroalkenes followed by isomerization of obtained spiranes without purification into nitriles by the high yield action of triethylamine in ethanol.
- An unusual rearrangement of indolyl nitroethanes to 2- (3-oxoindol-2-yl) acetonitriles was realized.
- The resulting compounds were tested for anticancer activity. 28 compounds - 4'H-spiro [indole-3,5'-isoxazole] were tested. Micromolar anticancer activity was detected in a number of these substances. One of these substances caused the differentiation of cells affected by neuroblastoma.
In 2018, we accidentally discovered the anti-mycobacterial activity of a fundamentally new bicyclic scaffold with a cyclopropane ring in its structure. Remarkably, this unusual peptidomimetic turned out to be non-toxic for other bacteria (both gram-positive and gram-negative), as well as for yeast, and some multicellular organisms, and tissues, including cell cultures of human cancer cells. Although the mechanism of action of these small molecules is currently unknown (the initial steps to elucidate this will be taken as part of the proposed scientific programme), the profile of activity and selectivity is very promising. Indeed, the selectivity of this new class of bioactive molecules is unique enough. Taking this into account, we can accept the hypothesis that the medication most likely targets one of the stages of mycolic acid FASII biosynthesis, which is unique to mycobacterial cells. Also, given the significant structural differences between our molecules and the known drugs targeting FASII, there is a big chance that we were able to detect a selective inhibitor for one of the stages of biosynthesis which was previously unused for therapy. The medication with the best performance at this moment has several structural elements that demonstrated a response during preliminary SAR tests, leaving the opportunity for significant optimization. After proper development, this study may lead to the creation of a highly active and highly selective second-line anti-mycobacterial drug that can be used to treat many resistant infections.
In addition to the importance of our research for medical chemistry discussed above, we undertook another important task, so far without a solution, related to the search for ways to stereoselectively cyclize middle cycles. Indeed, while there are a huge number of methods for cyclizing unstressed 5- and 6-membered cycles providing high stereo control, medium-sized stressed cycles (from 7- to 10-membered) are much more difficult to obtain - due to the significant energy of stressed transition state during cyclization, as well as an unfavorable decrease in entropy in a cyclic product compared with the acyclic starting compound. Also, the increased conformational freedom of the transition state makes it very difficult to control stereoselectivity in such cyclizations, which problem is usually solved by incorporating excessive steric hindrances or by organizing stricter pre-reaction complexes (usually in the coordination sphere of a metal - Lewis acid or transition metal catalyst). Even with these tricks, a strong dilution of the reaction mixture is usually required to slow down the competitive intermolecular processes leading to the formation of linear oligomeric products. Such a requirement often makes the reaction inconvenient for carrying out even in laboratory conditions, and completely unsuitable for industrial scaling.
As part of the ongoing project, we use various versions of the stereoselective metal template nucleophilic addition to cyclopropene-3-carboxamides developed in our laboratory. This approach is supposed to allow us to address most of the problems associated with the closure of medium cycles. The release of the enormous excess strain energy that occurs when a cyclopropene is attached to a double bond should by far exceed the much more modest requirements for the enthalpy needed to create a transannular medium-cycle strain. The presence of conformationally inhibited small cycle and carboxamide function in combination with a metal template effect should help make the geometry more rigid, which in turn will make it possible to design stereoselective cyclizations. Also, various follow-up transformations involving small ring cleavage could be incorporated, further increasing possible diversification of the products obtained via this synthetic strategy. Even if only partially developed, this approach will significantly improve the set of existing tools for stereoselective cyclization of medium cycles. For the period of implementation of the project, more than 25 papers were published, 7 of them in scientific journals indexed in the Web of Science Core Collection databases, 5 of them have the first quartile and 2 - the second one, and the following articles were published:
- Nitrostyrenes as 1,4-CCNO-dipoles: diastereoselective formal [4+1] cycloaddition of indoles. Aksenov A.V., Aksenov N.A., Aksenov D.A., Khamraev V.F., Rubin M. / Chemical Communications 2018. 54, 13260-13263. (Q1 IF 6.14).
- Metal-Templated Assembly of Cyclopropane-Fused Diazepanones and Diazecanones via exo-trig Nucleophilic Cyclization of Cyclopropenes with Tethered Carbamates. Maslivetc V.A., Frolova L.V., Rogelj S., Maslivetc A.A., Rubina M., Rubin M. / Journal of Organic Chemistry, (2019) 83 (22), pp. 13743−13753. (Q1, IF 4.75).
- Directed Cu(I)-Catalyzed Carbomagnesiation of 1‑Arylcycloprop-2-ene-1-carboxamides En Route to Densely Substituted Functionalized Cyclopropanes. Edwards A., Rubin M. / Journal of Organic Chemistry, (2019) 83 (22), pp. 13743−13753. (Q1, IF 4.75).
- Synthesis of Spiro[indole-3,5′-isoxazoles] with Anticancer Activity via a Formal [4 + 1]-Spirocyclization of Nitroalkenes to Indoles. Aksenov, A.V., Aksenov, D.A., Arutiunov, N.A., Aksenov, N.A., Aleksandrova, E.V., Zhao, Z., Du, L., Kornienko, A., Rubin, M. / Journal of Organic Chemistry, (2019) 84 (11), pp. 7123-7137. (Q1, IF 4.75).
- Preparation of Stereodefined 2-(3-Oxoindolin-2-yl)-2-Arylacetonitriles via One-Pot Reaction of Indoles with Nitroalkenes. Aksenov, A.V., Aksenov, D.A., Aksenov, N.A., Aleksandrova, E.V., Rubin, M. / Journal of Organic Chemistry, (2019) 84 (19), pp. 12420-12429.
- Electrophilically Activated Nitroalkanes in Reactions with Carbon Based Nucleophiles. Aksenov N.A., Aksenov A.V., Ovcharov S.N., Aksenov D.A., Rubin M. / Frontiers in chemistry, 2020, 8:77.
- A new series of acetohydroxamates shows in vitro and in vivo anticancer activity against melanoma Investigational New Drugs, Segat, G.C., Moreira, C.G., Santos, E.C., Heller, M., Schwanke, R.C., Aksenov, A.V., Aksenov, N.A., Aksenov, D.A., Kornienko, A., Marcon, R., Calixto, J.B. (2019). DOI: 10.1007/s10637-019-00849-6.
In the course of further implementation of the project we are planning to:
- develop a new general approach to the synthesis of isoxazoles containing a heterocyclic substituent at position 5 of isoxazole.
- develop a method for the synthesis of 3-aryl-2-cyanomethylindoles, based on the direct introduction of a cyanoalkyl group in position 2 of the indole with migration of the aryl substituent,
- perform studies on possibility of isoxazole cyclization. In particular, for the implementation of cyclopropane ring opening, magnesium derivatives of indoles will be obtained,
- synthesize indolylpropiohydroxamic acids by opening the ring in nitrocyclopropanes,
- obtain and test new indolylacetohydroxamic acids,
- develop new approaches to indolylacetohydroxamic acids, otherwise unavailable, and to a number of analogues of natural compounds by the reaction of indoles with nitroalkes in phosphoric acids in the presence of an oxidizing agent,
- develop a method of amination of indoles, based on the reaction of indoles with sodium azide in PFC. Amination reaction products will be involved in cascade transformations.
- conduct biological tests of obtained compounds to identify substances with high anti-cancer and other activity.
Prospects for practical use
The application of new approaches to preparation of indoles will make it possible to easily obtain a number of interesting compounds which are hard to obtain via traditional methods. The approach mentioned above will allow to construct new heterosystems with a combination of functional substituents and pharmacophore groups necessary for the design of anti-cancer drugs.
Biological tests of the obtained compounds will reveal substances with high anticancer activity, which cause differentiation of cells affected by neuroblastoma.