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Novogen Limited Message Board

  • moosefromoz moosefromoz Jan 23, 2013 10:57 PM Flag

    Triaxial

    Novogen’s starting point back in 1994 was a naturally-occurring compound called genistein. There was then (and still is) interest in the scientific community in this plant isoflavone as a potential anti-cancer agent.

    Genistein came to the attention of medical researchers in the early 1990s because of its ability to stop almost all forms of human cancer from growing and from forming blood vessels (angiogenesis), and to do so without any apparent effect on healthy cells. Genistein’s problem is that its anti-cancer activity is quite modest, plus the body breaks down the genistein quickly and efficiently; that is, its horsepower and staying power were too lacking to mark it as a useful anti-cancer agent.

    But its anti-cancer action marked it as compound of some considerable interest, leading Novogen to adopt a traditional pharmaceutical approach, viz. the adoption of an analog program intended to create a genistein analog that would retain genistein’s high selectivity against cancer cells, but at a much higher degree of potency, and which would not be prone to metabolism within the body.

    Initial libraries of genistein analogs created by Novogen chemists quickly identified the molecule’s pharmacophore. This was the two terminal OH groups on either end of genistein (the two ‘claws’ of the scorpion), which is the part of the molecule that we now know binds to the cancer cell. A library of 100 genistein analogs was made and screened for anti-cancer activity. Only one analog – NV06 – a very small structural variant of genistein, achieved the goal of increased anti-cancer activity and persistence in the body. The two structures are shown below with the key aprts of the molecule that fit the pharmacophore developed from Novogen’s initial library shown in red. NV06 is phenoxodiol (idrinoxil) which then went on to enter clinical studies.

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    • Phenoxodiol was never regarded by Novogen as the end-game, and the analog program continued in earnest, looking at relatively simple analogs of genistein and phenoxodiol in an effort to uncover even more potent drugs. That effort proved largely unrewarding.

      The breakthrough came about by serendipity, an unexpected and exciting result recognized by Andrew Heaton and his groups of scientists. To progress NV-06 through the various stages of clinical trials it had to be synthesized in large quantities in a pure form. The manufacture of any new drug has to be completed in accord with strict pharmaceutical Good Manufacturing Practices (GMP). One of the aspects of GMP is a requirement to identify any potential impurities at different stages of manufacture and to determine their relevance.

      In the manufacture of NV-06, an impurity was isolated and identified in the latter part of the manufacturing program. Careful isolation and identification of this impurity indicated that it had a dimeric isoflavone structure. In effect this was two of the scorpion heads joined at the neck. The team of scientists at Novogen was successful in isolating and purifying this material in sufficient quantities to determine its anti-cancer profile. Interestingly in comparison to NV-06 and the original drug library of single scorpion heads, the dual scorpion head compound was found to have superior anti-cancer activity.

      A hunt through the existing Novogen drug library indicated that this type of head-to-head scorpion impurity occurred in two different guises in the manufacture of other members of the original drug library. The drug-like properties of these dimeric compounds sent the drug discovery program on a new pathway, investigating how to manufacture head-to-head scorpion structures, not as impurities but as potential anti-cancer drugs in their own right.

      • 1 Reply to moosefromoz
      • The cornerstone of this project was the development of a new technology platform to manufacture these head-to-head scorpion structures. The first library that was made involved attaching the claw of one scorpion head to a second complete scorpion head. These experiments were successful and gave rise to a series of analogs that are in effect one complete scorpion head with just the claw of the 2nd scorpion head attached. This library of analogues included the compounds NV-128, NV-143 and NV-344.

        The Novogen drug development program reached a roadblock at that point because of some inherent problems with the technology. They were (a) it proving impossible to reproduce any of the complete head-to-head dimeric compounds that were being sought, and (b) being highly restricted by the range of chemical groups that could be added.

        The Triaxial technology platform started at that point with the following four aims:

        1. an ability to add a wider range of chemical groups, a crucial step in achieving the manufacture of full head-to-head scorpion structures;

        2. an ability to control the bend angle between different parts of the molecule;

        3. to produce novel and patentable families of compounds;

        4. to develop a method of drug manufacture requiring fewer and less expensive steps. Each step also being able to be scaled-up using readily available facilities.

        The key breakthroughs were achieving Aims #1 and 2. The ability to add a range of groups that where hitherto impossible under the Novogen technology platform, plus achieving control over the various bends in the molecule (but particularly the bend between the scorpion’s head and tail), generating new families of compounds of considerably greater complexity than simple benzopyrans such as genistein and phenoxodiol. These new compounds are termed superbenzopyrans.

        Each step of the new technology was developed to wherever possible complete at least two chemical transformations in the one reaction mixture, thereby fulfilling aim #4 and in so doing generating significant time and cost savings.

        The current CS range of superbenzopyran drugs is the result of that quantum leap in technology. One CS drug having been selected to enter clinical development without delay, with an analog program being actively pursued in an attempt to discover even more active and differently acting anti-cancer drugs.

 
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