Discovery and development of natural product-derived chemotherapeutic agents based on a medicinal chemistry approach

Abstract

Medicinal plants have long been an excellent source of pharmaceutical agents. Accordingly, the long-term objectives of the author's research program are to discover and design new chemotherapeutic agents based on plant-derived compound leads by using a medicinal chemistry approach, which is a combination of chemistry and biology. Different examples of promising bioactive natural products and their synthetic analogues, including sesquiterpene lactones, quassinoids, naphthoquinones, phenylquinolones, dithiophenediones, neo-tanshinlactone, tylophorine, suksdorfin, DCK, and DCP, will be presented with respect to their discovery and preclinical development as potential clinical trial candidates. Research approaches include bioactivity- or mechanism of action-directed isolation and characterization of active compounds, rational drug design-based modification and analogue synthesis, and structure-activity relationship and mechanism of action studies. Current clinical trial agents discovered by the Natural Products Research Laboratories, University of North Carolina, include bevirimat (dimethyl succinyl betulinic acid), which is now in phase IIb trials for treating AIDS. Bevirimat is also the first in a new class of HIV drug candidates called "maturation inhibitors". In addition, an etoposide analogue, GL-331, progressed to anticancer phase II clinical trials, and the curcumin analogue JC-9 is in phase II clinical trials for treating acne and in development for trials against prostate cancer. The discovery and development of these clinical trial candidates will also be discussed.

Figure 1

Flowchart for drug discovery and development of natural products-derived chemotherapeutic agents. Qian, K.; Nitz, T. J.; Yu, D.; Allaway, G. P.; Morris-Natschke, S. L.; Lee, K. H. In Natural Product Chemistry for Drug Discovery; Buss, A. D., Butler, M. S., Eds., RSC Publishing: Cambridge, UK, 2010; p 376. Reproduced by permission of The Royal Society of Chemistry.

Figure 2

Complementarity of chemistry and biology: medicinal chemistry is an art of combining chemistry and biology for drug discovery

Figure 3

Structures of cytotoxic natural sesquiterpene lactones from Elephantopus mollis

Figure 4

Structures of cytotoxic natural pseudoguaianolides from Helenium microcephalum

Figure 5

Rank order of cytotoxic potency of helenalin analogs with varying degrees of molecular unsaturation

Figure 6

Structure of bis(helenalinyl)glutarate

Figure 7

Structures of cytotoxic natural quassinoids from Brucea species

Figure 8

Structures of cytotoxic synthetic quassinoids

Figure 9

Structures of antileukemic natural flavonoids and lignan from Wikstroemia indica

Figure 10

Structures of cytotoxic synthetic fluorinated 2-phenyl-4-quinolones

Figure 11

Structures of cytotoxic psychorubrin and other quinone analogs

Figure 12

Structures of cytotoxic dithiophenedione analogs

Figure 13

Structures and antimitotic activity of colchicine, thiocolchicine, and thiocolchicone analogs

Figure 14

Structures of podophyllotoxin, etoposide, and teniposide

Figure 15

Structures of novel 4β-arylamino etoposide analogs

Figure 16

Structures of cytotoxic curcuminoids

Figure 17

Structures of cytotoxic tanshinones and neo-tanshinlactones

Figure 18

Structures of cytotoxic natural Tylophora alkaloids and synthetic PBT analogs

Figure 19

Mechanistic comparison of Tylophora alkaloids

Figure 20

Structures of conjugated paclitaxel analogs

Figure 21

Summary of the highlights of antitumor agents discovered by NPRL in clinical trials and preclinical studies

Figure 22

Structures of artemisinin and inactive, less active, and equipotent analogs

Figure 23

Structure of antibacterial/antifungal agent licensed by Rohm & Haas

Figure 24

Structures of betulinic acid, its natural precursor betulin, and its synthetic analog DSB

Figure 25

Summary of clinical development of 133, an anti-AIDS compound discovered by NPRL

Figure 26

Pharmacophores for anti-HIV maturation versus entry inhibitory 130-analogs

Figure 27

130-Derived HIV-1 entry inhibitors

Figure 28

Comparison of C-3 mono-, C-28 mono-, and C-3,28 di-substituted triterpene HIV-1 inhibitors

Figure 29

Structures of anti-HIV natural coumarin suksdorfin and synthetic analog DCK

Figure 30

Potent disubstituted analogs of 146

Figure 31

Biostereo-isomeric analogs of 146

Figure 32

Summary of preclinical development of DCK and DCP derivatives, anti-HIV compounds discovered by NPRL

Scheme 1

Synthesis of desmosdumotins B and C and analogs Reagents: a) NaOMe, RI; b) TMSCHHN₂; c) ArCHO, KOH; d) I₂, DMSO then BBr₃

Scheme 2

Synthesis of protoapigenone and analogs Reagents: a) MOMCl, K₂CO₃; b) KOH, 4-OBn-PhCHO; c) I₂, DMSO or Py; d) 10% Pd/CC, H₂; e) TAIB, CH₃CN/H₂O for R₃=OH or MeOH for R₃=OMe; f) 15% HCl/i-PrOH

Scheme 3

Synthesis of DCK analogs