Treatment of drug-resistant cancer with 2-aryl-2-(3-indolyl) acetohydroxamates
Patent Number: US9206124B2
Executive Summary:
General Description:
Our recent studies of a reaction of indole derivatives with β-nitrostyrenes in polyphosphoric acid (PPA) led to the discovery of an efficient synthesis of 2-aryl-2-(3-indolyl)acetohydroxamates. Although 2,2-diarylacetohydroxamates had been previously synthesized and studied for biological activities, compounds in which one of the two aromatic rings is an indole moiety had not been reported in the literature. Thus, 2-aryl-2-(3-indolyl)acetohydroxamate was revealed to be a new chemotype, prompting our thorough investigation of biological properties of compounds incorporating this structural feature. These studies led to the discovery of significant activity associated with a number of synthesized compounds against cancer cell lines displaying resistance to various types of proapoptotic stimuli as well as glioblastoma neurosphere stem-like cell cultures derived from patients. It was also found that the active analogues exhibited their antiproliferative activity through a cytostatic non-apoptotic mechanism of action and maintained their potency against multi-drug resistant cells, which are poorly responsive to important clinical cancer drugs taxol and vinblastine.
Strengths:
Weaknesses:
Patent Status:
Inventor Bios: Snezna Rogelj, Liliya Frolova
http://infohost.nmt.edu/~biology/people/faculty/s_rogeljWork/research.html
http://infohost.nmt.edu/~chem/frolova.html
Executive Summary:
- Invention Type: Therapeutic
- Patent Status: Active
- Patent Link: https://patents.google.com/patent/US9206124B2/
- Research Institute: New Mexico Technical Research Foundation
- Disease Focus: Apoptosis-Resistant Cancer
- Basis of Invention:
- How it works: 2-Aryl-2-(3-indolyl)acetohydroxamates (3, FIG. 1) were identified to be intermediates in our recently discovered transannulation of indoles to 2-quinolones carried out by reacting 2-substituted indoles with β-nitrostyrenes in PPA at 100° C. It was found that if the reaction temperature was kept at 70° C., compounds 3 could be isolated as the main reaction products (FIG. 1A, Tables 1 and 2). The reaction scope was found to allow for the introduction of a variety of substituents R1, R2, R3 and R4 into the 2-aryl-2-(3-indolyl)acetohydroxamate scaffold 3. In addition, the recognition of limited access to a number of specific substituted indoles that would be required for systematic structure-activity relationship (SAR) analyses prompted the development of an alternative route based on an in situ Fisher indole synthesis utilizing arylhydrazines 4 and ketones 5 (FIG. 1B). In this multicomponent variation, compounds 4 and 5 are reacted at 100° C. to allow for the indole formation and then the reaction temperature is lowered to 70° C. prior to the introduction of β-nitrostyrenes 2. Thus, the availability of two complementary approaches to compounds 3 permits the synthesis of analogues with the desired identity and positioning of substituents R1, R2, R3 and R4 on the 2-aryl-2-(3-indolyl)acetohydroxamate scaffold facilitating the development of these compounds as medicinal agents. Since the synthesized compounds have four diversification points, a four-dimensional tagging system is employed for labeling the products. Thus, the reaction of hydrazine 4aa with ketone 5f produces indole 1aaf, which in the subsequent reaction with nitrostyrene 2n affords hydroxamic acid 3aafn (see Experimental Section for these compounds).
- Lead Challenge Inventor: Snezna Rogelj, Liliya Frolova
- Inventors: Alexander V. Akensov, Snezna Rogelj, Liliya Frolova, Alexander Kornienko, Gabriel Avilucea
- Development Stage: Preclinical
- Novelty:
- Novel mechanism of action to induce apoptosis
- Clinical Applications:
- Treatment of a variety of cancers
General Description:
Our recent studies of a reaction of indole derivatives with β-nitrostyrenes in polyphosphoric acid (PPA) led to the discovery of an efficient synthesis of 2-aryl-2-(3-indolyl)acetohydroxamates. Although 2,2-diarylacetohydroxamates had been previously synthesized and studied for biological activities, compounds in which one of the two aromatic rings is an indole moiety had not been reported in the literature. Thus, 2-aryl-2-(3-indolyl)acetohydroxamate was revealed to be a new chemotype, prompting our thorough investigation of biological properties of compounds incorporating this structural feature. These studies led to the discovery of significant activity associated with a number of synthesized compounds against cancer cell lines displaying resistance to various types of proapoptotic stimuli as well as glioblastoma neurosphere stem-like cell cultures derived from patients. It was also found that the active analogues exhibited their antiproliferative activity through a cytostatic non-apoptotic mechanism of action and maintained their potency against multi-drug resistant cells, which are poorly responsive to important clinical cancer drugs taxol and vinblastine.
Strengths:
- Novel mechanism of action
Weaknesses:
- A lot of pro-apoptotic drugs on the market
Patent Status:
- Priority date: 2013-10-16
- Filing date: 2014-10-16
- Publication date: 2015-12-08
- Grant date: 2015-12-08
Inventor Bios: Snezna Rogelj, Liliya Frolova
http://infohost.nmt.edu/~biology/people/faculty/s_rogeljWork/research.html
http://infohost.nmt.edu/~chem/frolova.html
