Natural Products Chemical Modification: Importance in Drug Discovery (Part-II)

Chemical modification of morphine led to heroin (potent opioid analgesic by increasing blood brain barrier permeability), codeine (antitussive), Apo morphine (erectile dysfunction and Parkinson’s disease), hydromorphone (potent analgesic drug).

Similarly modification of Thebaine led to thebacon (Acedicon™ antitussive), oxycodone (narcotic analgesic), etorphine (analgesic 1,000-3,000 times more potent than morphine generally it used to immobilize elephants or large mammals), oxymorphone (opana®, powerful opioid analgesic), buprenorphine (treat to opioid addiction), oxymorphol (analgesic and antitussive).

Khellin was initially used as bronchodilator but found to cause nausea and vomiting. Chemical modification of Khellin led to chromolyn (used as sodium chromoglycate), which enabled the drug to stabilize cell membrane in the lungs to prevent the allergen induced release of substance ultimately seen as a cause for bronchoconstriction in allergic asthma patients.

Similarly, modification of natural product papaverine led to verapramil a drug to treat hypertension. Galegine isolated from Galega officinalis provided template for the synthesis of Metformin an anti-diabetic drug. Similarly clinical utility of podophyllotoxin as an antitumor agent largely have been abandoned because of its side effects like gastrointestinal toxicity and poor water solubility. However, structural modification led to development of new semisynthetic glucoconjugate analogues Etoposide, Teniposide. Salvinorin A (Salvia divinorum Mexican plant) is a hallucinogen, structural modification led to 2-ethoxymethyl salvinorin B (10 times stronger than salvinorin A), Herkinorin reduced kappa opiod action and instead act as µ-opioid receptor agonist. Another example of structural modification is development of prodrug Minnelide from Triptolide, developmet of CNB-001 from curcumin and development of colforsin from forskolin. Structural modification of Hesperdin (citrus fruit) to the development of diosmin for venous disease (chronic venous insufficiency), structural modification of Amygdalin to the development of Laetrile, structural modification of parthenolide led to development of dimethyl amino parthenolide, melampomagnolide B. In addition to that structural modification of thapsigargin led to the development of G-202 and structural modification of illudin S led to development of irofulven.

Despite of natural product modification, natural product mimics also contributed to drug discovery. Based on the observation that a nonapeptide (Glu-Try-Pro-Arg-Pro-Glu-Iie-Pro-Pro) from Viper venom caused lowering of blood pressure, new hypertensive agents were developed which are known by trade name “Prils” like Captopril, Enalapril, Lisinopril, Cilazapril, Spirapril. These constitute one of the most important classes of cardiovascular drugs. Likewise, drugs have been developed which involve synthetic molecules/materials from agents originally derived from plants. For example, Psuedoephedrine, originally derived from Ephedra sp., has been a model for the preparation of new synthetic drugs like Propronalol, Metaprolol, Atenolol, and development of Docetaxel from Paclitaxel, development of Navelbine (Vinorelbine) from Vinblastine, Flavopiridol from Rohitukine, Carfilzomib from Epoxomicin, Ivermectin from avermectin etc. The above example proves clearly that the structural modification of natural products has a greater role in Drug Discovery.