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Method for Immunomodulation of using Aza-podophyllotoxin derivatives

a technology of azapodophyllotoxin and immunomodulation, which is applied in the field of biological activity of azapodophyllotoxin derivatives, can solve the problems of limiting the structural activity relationship (sar) of podophyllotoxin, severe gastrointestinal side effects, and difficult selective transformation of the ome group present on the ring e of the starting lignan, so as to limit the breadth of application.

Inactive Publication Date: 2016-09-01
SISTEMA UNIVRIO ANA G MENDEZ
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes the use of a compound called AZP for modulating the immune system. The researchers tested the compound and found that it caused the release of certain proteins known as cytokines, which play a crucial role in immunity. The data showed that the compound was able to induce the release of a range of cytokines, including GCSF and IL6. This demonstrates the immune-stimulating effects of AZP. The technical effect of this patent is the discovery of a new compound that can be used to modify the immune system.

Problems solved by technology

However, it causes severe gastrointestinal side effects, due to epimerization at C2 to cis-lactone.
The structural complexity of podophyllotoxin has restricted most of the structural activity relationship (SAR) studied due to limitations in the derivatization of the parent natural compound.
Selective transformation of—OMe groups present on ring E of the starting lignan would be a very difficult task.
However, there are no published reports on the immunomodulatory activity of N-Hydroxyethyl-4-aza-didehydropodophyllotoxin or its derivatives.

Method used

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  • Method for Immunomodulation of using Aza-podophyllotoxin derivatives
  • Method for Immunomodulation of using Aza-podophyllotoxin derivatives
  • Method for Immunomodulation of using Aza-podophyllotoxin derivatives

Examples

Experimental program
Comparison scheme
Effect test

example 1

IL-6

[0032]IL-6 is secreted by macrophages after a stimuli like PAMPs. This cytokine has an important role mediating fever and the acute phase response. The acute phase response is an early-defense system activated by the onset of infection, trauma, inflammatory processes, neoplastia, stress, and some malignant conditions. “Miller-Keane Encyclopedia and Dictionary of Medicine, Nursing, and Allied Health”, Seventh Edition, (2003) by Saunders, an imprint of Elsevier, Inc.; and Cray et al., “Acute Phase Response in Animals: A Review”, Comp Med. 2009 December; 59(6): pp. 517-526. It has a critical role against bacterial infections, as it is required for the resistance mechanisms against the bacteria Streptococcus pneumonia.

[0033]Our data shows that IL-6 is produced by all the compounds tested in this project. Specifically, 184, 270, 257, 375, 261, and 1445 pg / mL of IL-6 was produced by AP311, AP312, AP102, AP103, AP104, and AP205. respectively. Among the tested compounds, AP205 induced ...

example 2

GCSF

[0034]GCSF is a glycoprotein produced by macrophages with the role of stimulating the production of granulocytes and stem cells from the bone marrow. It also has a role in the survival, proliferation, differentiation, and function of mature neutrophils and their precursors.

[0035]The therapeutic role of this cytokine has been commercially exploited by several pharmaceutical corporations. Specifically, cancer patients are in myelosuppression conditions, therefore, they lack of sufficient levels of white cells for disease control, making them susceptible to infections and sepsis. As GCSF has the capacity to produce granulocytes, it is used for the control of neutropenia in cancer patients, enhancing their quality of life. Moreover, during the hematopoietic stem cell transplant, GCSF is administered to the transplant donor to enhance the amount of hematopoietic stem cells before collecting by leukapheresis.

[0036]In our study, we observed levels of GCSF of 736, 858, 690, and 2336 pg / ...

example 3

IL-12

[0038]IL-12 is an heterodimer coded by two genes (p35 and p40). The p70 heterodimer is the active form. IL-12 is involved in the differentiation of the naive T-cells to Th1. In this sense, this cytokine has the capacity of reducing the IFN-suppression mediated by IL-4.

[0039]During the innate immune response, the macrophages are the main responsible for the production of IL-12. It stimulates the production of IFN-gamma from T and NK cells.

[0040]One of the most important roles of IL-12 is its capacity to mediate the cytotoxic activity of both, the NK and the CD8+ T-cells. IFN-gamma has an anti-angiogenic activity, blocking the formation of new blood vessels, which supports tumor growth. As IL-12 induces the release of IFN-gamma, this cytokine has an indirect antineoplastic role.

[0041]Cultured splenocytes induced 13, 29, 21, 22, and 60 pg / mL when stimulated with AP312, AP102, AP103, AP104, and AP205.

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Abstract

Disclosed is the novel use of some Aza-podophyllotoxin derivatives (AZPs) for modulation of the immune system (immunomodulation), including a method for modulating an immune response comprising administering to a subject an effective amount of at least one Aza-podophyllotoxin derivative of general formula wherein A-ring is selected from the group consisting of 1,3-dioxolane, cyclopentane, 1,4-dioxane, one methoxy, two methoxys, and ethyl; and wherein E-ring is selected from the group consisting of dimethoxyanisole, veratrol, anisole, benzene, syringol, bromobenzene, chlorobenzene, 1,2-dichlorobenzene, 2,3-dimethoxybenzene, 3,4,5-trimethoxybenzene.

Description

BACKGROUND OF THE INVENTION[0001]1. Field of the Invention[0002]The present disclosure relates to the biological activity of aza-podophyllotoxin derivatives. More particularly, the use of aza-podophyllotoxin derivatives for modulation of the immune system.[0003]2. Discussion of the Background[0004]The innate immune response is the first line of defense against infections. The cells of the innate immune system have the capacity to recognize generic structural patterns present in pathogens called Pathogen Associated Molecular Patterns (PAMPs), and mounts an immediate immune response against these agents. This system works as a barrier that protects mammals against many ailments including infectious diseases, activate the complement system, recruits cells of the immune system to induce the process of inflammation, identifies and remove pathogens, and one of the most important features of this system, which is to activate the adaptive immune response. The term “ailment” as used in this ...

Claims

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Application Information

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IPC IPC(8): A61K39/00A61K31/4741
CPCA61K31/4741A61K39/00
Inventor KUMAR
Owner SISTEMA UNIVRIO ANA G MENDEZ
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