Current Developments in the Discovery and Design of New Drug Candidatesfrom Plant Natural Product Leads
Natural Products Laboratory, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7360 Received August 14, 2003
This review article will emphasize recent research in the Natural Products Laboratory, School of Pharmacy,University of North Carolina at Chapel Hill, on various classes of plant-derived compounds that possesspotent antitumor or anti-HIV activity. These compounds were obtained by bioactivity- and mechanismof action-directed isolation and characterization coupled with rational drug design-based modificationand analogue synthesis. Structural modification, SAR, and mechanism of action studies are discussed.From ancient to modern times, herbs and other plantshave been used as medicinal agents, first only on a folkloricbasis and later developed on a scientific basis into singleagent drugs, such as the antiasthmatic drug ephedrinefrom
The drug discovery and developmentprogram in the author’s Natural Products Laboratory(NPL) and those of other researchers worldwide use plantsas an essential route to new pharmaceutical leads.
A major objective of the NPL is the preclinical develop-ment of bioactive natural products and their analogues aschemotherapeutic agents, including plant-derived antitu-mor agents, particularly novel etoposide analogues, anti-HIV compounds and analogues, as well as antimalarial,antifungal, antiviral, and anti-inflammatory agents. Chi-nese herbal medicine is the primary, although not sole,source of new leads. The three main research approachesare (a) bioactivity- or mechanism of action-directed isolationand characterization of active compounds, (b) rational drugdesign-based modification and analogue synthesis, and (c)mechanism of action studies. Drug discovery is an iterativeprocess of lead discovery (i.e., isolation of bioactive leadcompound(s) from these natural sources) coupled with leadimprovement (rational design and synthesis of new ana-logues to improve pharmacological profiles). After selectionof a new lead, drug development continues outside of theacademic laboratories through preclinical studies (toxicol-ogy, formulation, and production) followed by clinical trials.In the academic laboratory, drug design/structure modifi-cation employs several tools to identify the optimumchemotherapeutic agent:(a) structure
activity relationship (SAR) studies includ-ing both qualitative and quantitative SAR,(b) mechanism of action studies including drug receptorinteractions and specific enzyme inhibitions,(c) drug metabolism studies including identification of bioactive metabolites and blocking of metabolic inactiva-tion,(d) molecular modeling studies including determinationof 3D pharmacophores,(e) combinatorial chemistry, including creation of peptideand nonpeptide libraries to generate new leads.The discussion below will present several of these agentsas well as prior and new lead identification and researchperformed in the NPL.
Plant-Derived Antineoplastic Agents and TheirAnalogues as Clinical Anticancer Drugs (Figures1
Many plant antitumor agents are used as clinicalanticancer drugs: in the United States (in chronologicalorder) vinblastine (Velban,
), vincristine (Oncovin,
), etoposide (VP-16,
), paclitaxel (Taxol,
), docetaxel (Taxotere,
), and irinotecan (Camptosar,
) andmany others in China, including 10-hydroxycamptothecin(
) and homoharringtonine (
) (Figure 1).Vinblastine (
) and vincristine (
) are major drugs usedto treat Hodgkin’s lymphoma and acute childhood leuke-mia. They are natural alkaloids isolated from
(L.) G. Don (Apocynaceae) or
L.(Chinese medicine: “Chang Chung Hua”).
Among numer-ous synthetic analogues designed to have activity againstother tumor types or fewer side effects, Navelbine (
)(vinorelbine) was developed by Burroughs Wellcome andis used against non-small cell lung and advanced breastcancers.
This compound is a synthetic analogue of
, buthas a nine-membered rather than an eight-membered Cring and a dehydrated D ring.
The Chinese tree
contains the natural anticancer alkaloids camp-tothecin (
) (Figure 2) and 10-hydroxycamptothecin (
which are used to treat gastric, rectal, colon, bladder, liver,and head and neck cancers in the People’s Republic of China. However, synthetic derivatives, including topotecan(
and irinotecan (
were developed toanswer water solubility problems of the natural alkaloids.They contain amino groups that can form more solublehydrochloride salts; for example, compound
is 100-foldmore water-soluble than
. All natural and syntheticcamptothecins exert their anticancer activity by inhibitingthe enzyme topoisomerase I (topo I). The NPL synthesizeda series of water-soluble 7-(acylhydrazono)formyl camp-tothecins.
with a 7-(
-tyrosylhydrazono)group and four others were more potent than
ininhibiting DNA topo I and causing protein-linked DNAbreaks, but were less toxic in several cancer cell lines.Similarly, the NPL also chemically linked camptothecin(
) with paclitaxel (
), a natural antimitotic anticanceragent, through a variable length
Dedicated to the late Dr. Monroe E. Wall and to Dr. Mansukh C. Waniof Research Triangle Institute for their pioneering work on bioactive naturalproducts.
Antitumor Agents 231 and Anti-AIDS Agents 59. Presented, in part,at the 43rd Annual Meeting of the American Society of Pharmacognosy andthe 3rd Monroe E. Wall Symposium on July 28, 2002, in New Brunswick,NJ.* To whom correspondence should be addressed. Tel: 919-962-0066.Fax: 919-966-3893. E-mail: email@example.com.
J. Nat. Prod.
10.1021/np030373o CCC: $27.50 © 2004 American Chemical Society and American Society of PharmacognosyPublished on Web 12/03/2003