Synthetic rigidin analogues as anticancer agents, salts, solvates and prodrugs thereof, and method of producing same
Patent Number: US9334280B2
Executive Summary:
General Description:
The present invention describes novel hypoxanthine-like analogues of marine alkaloids rigidins. The rigidins incorporate the pyrrolo[2,3-d]pyrimidine ring system, which is considered a “privileged medicinal scaffold” (PMS). PMSs are molecular frameworks that are seemingly capable of serving as ligands for a diverse array of targets. The pyrrolo[2,3-d]pyrimidine ring system is analogous to the purine framework and, in addition to the rigidins, it is also a common motif in several other natural products, such as the nucleoside anticancer antibiotics tubercidin, toyocamycin, sangivamycin. Thus, the rigidins are an unexplored class of marine alkaloids that have a high potential for multiple biological activities.
Evaluation of these synthetically prepared alkaloids against several cancer cell lines revealed very weak antiproliferative activities (>100 micromolar IC50 values). The current discovery deals with the finding that an alteration of this reported synthetic methodology to a novel four-component reaction leads to the preparation of rigidin analogues possessing a previously unknown hypoxanthine-like skeleton. Further evaluation of these compounds against several cancer cell lines revealed a marked and unexpected potent antiproliferative effect at extremely low concentrations.
Scientific Progress:
The synthesized compounds of Formula I were evaluated for antiproliferative activity against a panel of cancer cell lines, including human HeLa cervical and MCF-7 breast adenocarcinomas. Many of the analogues exhibited nanomolar potency, characteristic of the clinically used anticancer agents.
Future Directions:
Strengths:
Patent Status:
Publications:
https://patents.google.com/patent/US7407967B2/
https://patents.google.com/patent/US6403636B1/
Inventor Bios: Snezna Rogelj, Liliya Frolova, Alexander Vladimir Kornienko
http://infohost.nmt.edu/~biology/people/faculty/s_rogeljWork/research.html
http://infohost.nmt.edu/~chem/frolova.html
http://www.txstate.edu/chemistry/people/faculty-alpha/kornienko.html
Executive Summary:
- Invention Type: Therapeutic
- Patent Status: Granted
- Patent Link: https://patents.google.com/patent/US9334280B2/
- Research Institute: New Mexico Tech, Texas State University
- Disease Focus: Glioblastoma, Melanoma
- Basis of Invention: Synthetic rigid analogues (Rigidins) as anticancer agents, salts, solvates and prodrugs, and method to produce these agents
- How it works: Cell death, cell cycle arrest in G1, targeting of actin or tubulin as well as histone deacetylase (HDAC) inhibition proposed
- Lead Challenge Inventor: Snezna Rogelj, Liliya V Frolova, Alexander Vladimir Kornienko
- Inventors: Igor V. Magedov, Snezna Rogelj, Liliya V Frolova, Alexander Vladimir Kornienko
- Development Stage: In vitro data in HeLa and MCF-7 cell line
- Novelty:
- The Rigidins incorporate the pyrrolo[2,3-d]pyrimidine ring system, which is considered a “privileged medicinal scaffold” (PMS). PMSs are molecular frameworks that are seemingly capable of serving as ligands for a diverse array of targets
- Clinical Applications:
- Treatment of Glioblastoma and melanoma
- Treatment of cervical, brain, breast, lung, head and neck and colon cancer
General Description:
The present invention describes novel hypoxanthine-like analogues of marine alkaloids rigidins. The rigidins incorporate the pyrrolo[2,3-d]pyrimidine ring system, which is considered a “privileged medicinal scaffold” (PMS). PMSs are molecular frameworks that are seemingly capable of serving as ligands for a diverse array of targets. The pyrrolo[2,3-d]pyrimidine ring system is analogous to the purine framework and, in addition to the rigidins, it is also a common motif in several other natural products, such as the nucleoside anticancer antibiotics tubercidin, toyocamycin, sangivamycin. Thus, the rigidins are an unexplored class of marine alkaloids that have a high potential for multiple biological activities.
Evaluation of these synthetically prepared alkaloids against several cancer cell lines revealed very weak antiproliferative activities (>100 micromolar IC50 values). The current discovery deals with the finding that an alteration of this reported synthetic methodology to a novel four-component reaction leads to the preparation of rigidin analogues possessing a previously unknown hypoxanthine-like skeleton. Further evaluation of these compounds against several cancer cell lines revealed a marked and unexpected potent antiproliferative effect at extremely low concentrations.
Scientific Progress:
The synthesized compounds of Formula I were evaluated for antiproliferative activity against a panel of cancer cell lines, including human HeLa cervical and MCF-7 breast adenocarcinomas. Many of the analogues exhibited nanomolar potency, characteristic of the clinically used anticancer agents.
Future Directions:
- Pre-clinical studies on the potency and efficacy of cancer treatment using rigidins
Strengths:
- Natural product derivatives which targets molecular mechanism of cell death and cell cycle
Patent Status:
- Priority date: 2012-11-16
- Filing date: 2015-04-23
- Publication date: 2016-05-10
- Grant date: 2016-05-10
Publications:
https://patents.google.com/patent/US7407967B2/
https://patents.google.com/patent/US6403636B1/
Inventor Bios: Snezna Rogelj, Liliya Frolova, Alexander Vladimir Kornienko
http://infohost.nmt.edu/~biology/people/faculty/s_rogeljWork/research.html
http://infohost.nmt.edu/~chem/frolova.html
http://www.txstate.edu/chemistry/people/faculty-alpha/kornienko.html