Natural products: a continuing source of novel drug leads

Abstract

Background: Nature has been a source of medicinal products for millennia, with many useful drugs developed from plant sources. Following discovery of the penicillins, drug discovery from microbial sources occurred and diving techniques in the 1970s opened the seas. Combinatorial chemistry (late 1980s), shifted the focus of drug discovery efforts from Nature to the laboratory bench.

Scope of review: This review traces natural products drug discovery, outlining important drugs from natural sources that revolutionized treatment of serious diseases. It is clear Nature will continue to be a major source of new structural leads, and effective drug development depends on multidisciplinary collaborations.

Major conclusions: The explosion of genetic information led not only to novel screens, but the genetic techniques permitted the implementation of combinatorial biosynthetic technology and genome mining. The knowledge gained has allowed unknown molecules to be identified. These novel bioactive structures can be optimized by using combinatorial chemistry generating new drug candidates for many diseases.

General significance: The advent of genetic techniques that permitted the isolation / expression of biosynthetic cassettes from microbes may well be the new frontier for natural products lead discovery. It is now apparent that biodiversity may be much greater in those organisms. The numbers of potential species involved in the microbial world are many orders of magnitude greater than those of plants and multi-celled animals. Coupling these numbers to the number of currently unexpressed biosynthetic clusters now identified (>10 per species) the potential of microbial diversity remains essentially untapped.

Fig. 1

Drugs based on traditional medicine leads (khellin, sodium chromoglycate, galegine, metformin, papaverine, verapamil)

Fig. 2

Natural antimalarial agents and analogues Quinine, chloroquine, mefloquine, artemisinin, OZ277, Dimeric analogue

Fig. 3

Plant-derived anticancer agents Vinblastine / vincristine, Etoposide, Paclitaxel, Taxotere, Cabazitaxel, Camptothecin / 9-NH₂, 9-NO₂ / Topotecan / Irinotecan / Belotecan, Maytansine

Fig. 4

Ecteinascidin 743 (Yondelis^®) and its semisynthetic precursor

Fig. 5

Halichondrin B, Eribulin, Bryostatin 1

Fig. 6

Drugs from Microbes Cephalosporins, cyclosporins, rapamycin, statins

Fig. 7

Microbial-Derived Anticancer Agents Daunomycin, bleomycin A2, mitomycin C, calicheamicin

Fig. 8

Epothilone anticancer agents Epothilones A–D, ixabepilone, sagopilone didehydroepothilone D, isoxazolefludelone

Fig. 9

Chitin and Glucan Inhibitors Nikkomycin Z, Caspofungin, Anidulafungin, Micafungin

Fig. 10

Drugs from amphibian, reptilian and human sources Teprotide, captopril, epibatidine, Byetta^®, liraglutide

Fig. 11

Sources of Drugs

Fig 12

Natural products and the cell cycle

Fig. 13

Natural Products from Antarctic sources Variolins, Palmerolide

Fig 14

Natural products from heterologous gene expression, extremophiles and endophytes Pantocin, berkeleydione, berkeleytrione, ambuic acid, aspochalasins, terrequinone

Fig. 15

Examples of novel microbial natural products Salinosporamide, marinomycins A-D, maytansine, pederin, onnamide, rhizoxin

Fig. 16

Products of Total Synthesis Diazonamide, discodermolide, TZT-1027/auristatin PE, E-7974

Fig. 17

Products of Diversity-Oriented and Parallel Synthesis and Privileged Structures Dysidiolide, galanthamine, psammaplin, sarcodictyin, 2,2-dimethyl-2H-benzopyran, benzopyrans plus cyanostilbene substitution

Fig. 18

New compounds from a variety of approaches ECO 0501, chivosazol, platensimycin, platencin, phomallenic acid C, lucensimycin A, (−)-adamantaplatensimycin

Fig. 19

Carfilzomib, Epoxomicin