Synthesis of 3-dehydroxy-5-epi-collinoketone and its cognitive benefits by reducing aggregates of amyloid-β and tau

12 August 2025, Version 1
This content is an early or alternative research output and has not been peer-reviewed by Cambridge University Press at the time of posting.

Abstract

Collinolactone, featuring a 7/10/6 tricyclic core, has been proposed to be biosynthesized via a transannular [6+4] cycloaddition reaction. Besides its intriguing architecture, collinolactone holds pharmaceutical promises due to its ability to disrupt amyloid-β (Aβ) and tau aggregation, which are specifically found as disease culprits in the brains of Alzheimer’s disease (AD) patients and are key targets in current drug discovery efforts. However, challenges associated with its acquisition from a natural source and limited pharmacokinetic properties have hampered its further studies. Herein, we report the design, synthesis, and evaluation of 3-dehydroxy-5-epi-collinoketone, a collinolactone derivative with improved pharmacokinetics for AD treatment. A stereoselective transannular [6+4] cycloaddition efficiently constructed the tricyclic core, allowing its scalable synthesis. AI-assisted simulations predicted superior binding of 3-dehydroxy-5-epi-collinoketone to Aβ and tau aggregates compared to collinolactone. In vitro studies confirmed its inhibition and dissociation of Aβ and tau fibrils, while in vivo experiments in AD mouse models showed substantial amelioration of cognitive functions and Aβ/tau-associated pathology.

Keywords

collinoketone
Alzheimer’s disease
[6+4] cycloaddition
amyloid-β
tau protein

Supplementary materials

Title
Description
Actions
Title
Supporting Information
Description
Experimental and Computational Procedures and Physical Data for Synthesized Compounds. Copies of NMR Spectra of Isolated and Synthesized Compounds
Actions

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting and Discussion Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.
Comment number 2, Greta Eliza: Nov 09, 2025, 00:58

I was diagnosed with Parkinson’s disease four years ago. For over two years, I relied on Levodopa and several other medications, but unfortunately, the symptoms kept getting worse. The tremors became more noticeable, and my balance and mobility started to decline quickly. Last year, out of desperation and hope, I decided to try a herbal treatment program from NaturePath Herbal Clinic. Honestly, I was skeptical at first, but within a few months of starting the treatment, I began to notice real changes. My movements became smoother, the tremors subsided, and I felt steadier on my feet. Incredibly, I also regained much of my energy and confidence. It’s been a life-changing experience I feel more like myself again, better than I’ve felt in years.If you or a loved one is struggling with Parkinson’s disease, I truly recommend looking into their natural approach. You can visit their website at www.naturepathherbalclinic.com. info@naturepathherbalclinic.com

Comment number 1, Jasmine Craven: Aug 15, 2025, 07:47

My husband was diagnosed with Alzheimer’s disease at 55; he would hallucinate and have conversations with who he was seeing. Last year he turned 64 and was no longer able to walk; his speech was becoming impaired. The doctor prescribed Seroquel. It helped, but not for long. Around January this year we started him on the UINEHEALTH CENTRE Neuro x program that was introduced to us by his primary care doctor, 2 months into treatment he improved dramatically. At the end of the full treatment course, the disease is totally under control. No case of dementia, hallucination, memory loss, the disease is totally under control. Reach them at www. uinehealthcentre. net I hope someone finds it helpful.