In spite of the unparalleled advances in drug discovery, developing a safe, effective and economical therapy for treating inflammatory conditions still presents a major challenge.

The beguiling ability to treat fever and pain can be traced back to 3.5 thousand years ago, when the Greek physician Hippocrates prescribed an extract from willow bark and leaves. Later in the 17th century, the biologically active substance of the willow bark, salicin (or salicylic acid), was identified in Europe through chemical degradation. The Kolbe company, operating at that time in Germany (in 1860), started scaling up the production of salicylic acid.

However, salicylic acid was associated with gastrointestinal (GI) irritation due to its acidic nature. Hence, the more palatable acetylsalicylic acid, now known commercially as aspirin, was launched in the market by Bayer in 1899.

Today, medication of inflammatory-related diseases is largely based on interjecting the action of mediators that propel the host’s response to injury. Non-steroidal anti-inflammatories, steroids and antihistamines, for instance, were developed on this concept.

The success of non-steroidal anti-inflammatory drugs (NSAIDs) in remedying various inflammatory conditions such as rheumatoid arthritis and osteoarthritis supported the hypothesis that blocking the enzyme prostaglandin H synthase or cyclooxygenase (COX) may be the key to the discovery of anti-inflammatory drugs.

Sadly, widespread NSAID use is associated with GI irritations and toxicities, making it a chief problem during long-term therapy.

The good news is that several medical reports have shown that traditional NSAIDs may fight off cancer. For example, the commercial anti-pain drugs sulindac and indomethacin show therapeutic effects against colorectal cancer.

Then it was discovered that an enzyme isoform – COX-2 – is present at high levels in a wide variety of cancer tissues, such as colon, breast, prostate, and pancreas. Moreover, it seems to control many cellular and other biological processes.

Thus, selective COX-2 drugs have been comprehensively explored in the treatment and preclusion of a variety of cancers. COX-2 inhibitors block COX-2 enzyme and not the COX-1 enzyme, thus impending the production of COX-2 which is more often the cause of pain and swelling of inflammation and other painful conditions. These drugs are different from traditional NSAIDs which usually block both COX-1 and COX-2 enzymes.

Though the selective COX-2 inhibitor commercial drug celecoxib induces programmed cell death in human prostate cancer cell lines, while the use of rofecoxib in preventing the recurrence of colon polyps was associated with adverse cardiovascular incidences. This puts a shadow of doubt on the long-term use of selective COX-2 inhibitors on cancer chemoprevention, and highlights the need to develop anti-inflammatory and analgesic agents that do not put patients at risk for gastrointestinal irritation or heart attack.

In our search for such drugs, we became interested in finding excellent acceptor-driven biological activity. The prevalence of unsaturated five-membered oxocarbocyclic motifs in anti-inflammtory and anti-cancer natural products and other bioactive compounds provides stimuli to discover potential anti-inflammatory and anti-cancer agents through a diversity-oriented synthesis approach.

Cyclopentanone platforms are present among natural and non-natural anti-inflammatory and anti-cancer compounds. Such substances play important roles in chemistry and biology because they are susceptible to addition reactions with biological groups present in proteins and enzymes associated with cancer-cells and inflammatory factors. Many biologically active cyclopentenone derivatives have been identified from nature (e.g. marine and terrestrial-derived fungi, liverwort, and plants) and block diverse biological activities, including anti-cancer, anti-inflammatory, cycloxyenase 2 (COX-2) inhibitory, cytotoxic, antimicrobial, anti-pigment, and plant growth-regulatory activities.

Currently in drug discovery, irreversible binding in active sites has proven to be one answer to drug resistance in cancer treatment. Overall, compounds containing the unsaturated carbonyl unit possess multiple biological activities that could be transferred into novel pharmaceutical agents. It has been shown that cancer and inflammatory conditions are connected, which makes these compound types even more attractive as therapeutic agents. The ability of unsaturated carbonyl to modify active site cysteines, resulting in irreversible inhibition of an enzyme is an emerging area in drug discovery.

The diversity-oriented synthesis (DOS) approach to construct a variety of 4-heterocyclopentenone derivatives allows the preparation of new compounds with increased and promising anti-inflammatory activity. Extensive literature search provides little evidence on DOS studies related to anti-inflammatory and cytostatic unsaturated cyclopentanones.

Our study hopes to synthetically prepare a variety of simple, low-molecular weight, functionalized, cyclopentanone derivatives with promising anti-inflammatory activity targeting enzymes involved in the inflammatory biochemical cascades such as COX and anti-cancer activity against a selected panel of cell-lines. The products that will be identified may feature new and unusual biological mechanism which would be high interest to medicinal chemists. In addition, the new structures generated would be viable templates for generating further a library of synthetic derivatives with improved potency.

NSAIDs embody an important type of compound to treat pain and cancer. The fast discovery of selective COX-2 inhibitors and anti-cancer compounds can be ascribed to rational drug design strategies. Sadly, the cardiovascular (CNS) side effects related with selective COX-2 inhibitors underscore the drawbacks that may be confronted in this drug discovery project.

Indeed, in spite of the unparalleled advances in drug discovery, developing a safe, effective, and economical therapy for treating inflammatory conditions still presents a major challenge.


Written by: 
Allan Patrick g. Macabeo
University of Santo Tomas

Published by:Department of Science and Technology - Science and Technology Information Institute (DOST-STII)