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Polyamine Analogs Polyamines such as putrescine, spermidine and spermine are naturally occurring, positively charged compounds found in virtually all living cells. These compounds bind to DNA and have been implicated in a number of crucial cellular processes such as cell division, differentiation and membrane function. It is known that the inhibition of polyamine synthesis, or their depletion from cells, stops cell growth. Since cell division is essential for cancer growth, scientists have speculated that inhibitors or analogs of these compounds might have potential as therapeutic treatments for cancers. 
The cytotoxic potential of inhibitors of the polyamine synthesis pathway has long been recognized and extensively investigated. An inhibitor of the enzyme ODC, (ornithine decarboxylase), has been developed and approved by the FDA. However, other attempts to inhibit this pathway have been elusive. Principally, this is because the pathway is so crucial to cell function that target cells tend to find ways to circumvent the inhibitory effects of most drugs acting at any single step.Another strategy is to use polyamine analogs: compounds that would mimic the natural polyamines but have modified function. While several potential modes of actions of polyamine analogs have been suggested, their ability to displace the natural polyamines from their DNA binding sites is the most likely mechanism of action. This would lead to a cessation of cell growth or cell destruction, since the polyamine analogs would be biologically inactive or have altered function. Despite the promise of early polyamine analogs, there were seemingly limited structural changes that could be made to the natural polyamine molecules without having the cell recognize them as ‘foreign’. Accordingly, the discovery and development of polyamine analogs was initially limited to first generation compounds, i.e., simple analogs of the natural polyamines. SLIL has overcome these obstacles, and is the only company to develop second, third and fourth generation polyamine analogs. These new drug classes are subject to SLIL patent filings or exclusive patent licenses. 
One of the important techniques used by SLIL scientists to create these new polyamine classes was conformational restriction.Conformational restriction is a technique that has been applied by scientists to a variety of other drugs. Essentially, it involves designing minute chemical alterations into compounds to restrict the molecular conformation (shape) which they may assume. This led to the second generation of polyamine analogs. SLIL now has several Lead Compounds in this class, and the first is now approved to commence a Phase I/II human clinical trial. The Company has also used other drug design techniques in its quest for effective polyamine analogs. One technique is to create longer chain polyamines that we designate as oligoamines - our third generation of compounds. Most recently, and in conjunction with the University of Zurich, a fourth generation of cyclic polyamines was discovered.
All Lead Compounds have completed in vitro screening for various indications and are available for preclinical development. While the primary therapeutic opportunity for the polyamine compounds is cancer, the drugs have been shown to be effective against a variety of proliferating (rapidly growing and dividing) cells, including various parasitic organisms. Thus far, SLIL’s portfolio of polyamine analogs has shown therapeutic promise for the following diseases:
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