Natural products (NP’s) continue
to represent an excellent source for lead structures in drug discovery. In
between 1981-2002 only 5% NCE were FDA approved natural products and 23% were natural
product derivatives. There are only few
cases, where NPs serve directly as drugs, but many of the drugs are the
structural analogues and or mimics. For a better drug or lead compound, the
molecule should possess not only high potency but also contain other properties
like being non-toxic, oral bioavailability (solubility, membrane permeability)
and with efficient ADME (Absorption, Distribution, Metabolism, and Excretion).
To address these issues, structural modification of NPs has been undoubtedly
playing pivotal role for the development of efficient modern medicine.
Structural analogues of natural products can give inputs for the clear picture
of molecular mechanistic to a medicinal chemist.
Literature is full of examples
wherein the modification of a natural product has led to a drug with optimized
or minimized toxicities, better drug delivery or higher potency. Artemisinin is
only sparingly soluble in water or oil and not well absorbed by the
gastro-intestinal tract. Chemical modification of artemisinin led to more
potent, better bioavailable analogues such as artemether, arteether, sodium
artesunate, fluoroanilide derivative.
Structural modification of
betulinic acid resulted in the discovery of most potent anti-HIV drug 3-O-(3’,
3’-dimethylsuccinyl)-betulinic acid (bevirimat, DSB, PA-457), another
triterpenoid structural modification led to development of bardoxlone methyl for
type 2 diabetes mellitus.
Therapeutic application of
unmodified camptothecin is hindered by very low solubility in aqueous media,
high toxicity, and rapid inactivation through lactone ring hydrolysis at
physiological pH. Chemical modification of
camptothecin led to more water-soluble analogs topotecan (Hycamtin), irinotecan
(Camptosar).
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