David Brian Camp

Drug-like Properties: Guiding Principles for the Design of Natural Product Libraries

While natural products or their derivatives and mimics have contributed around 50% of current drugs, there has been no approach allowing front-loading of chemical space compliant with lead- and drug-like properties. The importance of physicochemical properties of molecules in the development of orally bioavailable drugs has been recognized. Classical natural product drug discovery has only been able to undertake this analysis retrospectively after compounds are isolated and structures elucidated. The present approach addresses front-loading of both extracts and subsequent fractions with desired physicochemical properties prior to screening for drug discovery. The physicochemical profiles of natural products active against two neglected disease targets, malaria and African trypanosomiasis, are presented based on this strategy. This approach can ensure timely development of natural product leads at a hitherto unachievable rate.

Antimalarial activity of azafluorenone alkaloids from the Australian tree Mitrephora diversifolia.

Mass-directed isolation of the CH2Cl2/MeOH extract from the roots of the Australian tree Mitrephora diversifolia resulted in the purification of the new azafluorenone alkaloid 5,8-dihydroxy-6-methoxyonychine (1) together with the known natural product 5-hydroxy-6-methoxyonychine (2). The structures of 1 and 2 were determined by extensive 1D and 2D NMR and MS data analyses. Both compounds were isolated during a drug discovery program aimed at the identification of new antimalarial leads from a prefractionated natural product library. When tested against two different strains of the parasite Plasmodium falciparum (3D7 and Dd2), 2 displayed IC(50) values of 9.9 and 11.4 microM, respectively, while 1 showed minimal activity.

Antitrypanosomal Cyclic Polyketide Peroxides from the Australian Marine Sponge Plakortis sp.

Bioassay-guided fractionation of the crude extract from the Australian marine sponge Plakortis sp. led to the isolation of two new cyclic polyketide peroxides, 11,12-didehydro-13-oxo-plakortide Q (1) and 10-carboxy-11,12,13,14-tetranor-plakortide Q (2). Antitrypanosomal studies showed that compound 1 had an IC(50) value of 49 nM against Trypanosoma brucei brucei, and compound 2, where a carboxylic acid is present in the side chain, had a 20-fold reduction of activity. 11,12-Didehydro-13-oxo-plakortide Q (1) is the most active peroxide isolated so far against T. b. brucei, and it indicates the potential therapeutic value of this class of compounds.

Antimalarial bromotyrosine derivatives from the Australian marine sponge Hyattella sp.

A drug discovery program aimed at identifying new antimalarial leads from a prefractionated natural product library has resulted in the identification of a new bromotyrosine alkaloid, psammaplysin G (1), along with the previously isolated compound, psammaplysin F (2). When tested against two different strains of the parasite Plasmodium falciparum (Dd2 and 3D7), 2 displayed IC(50) values of 1.4 and 0.87 microM, respectively, while 1 showed 98% inhibition at 40 microM against the chloroquine-resistant (Dd2) strain of P. falciparum.

Antimalarial activity of pyrroloiminoquinones from the Australian marine sponge Zyzzya sp.

A new bispyrroloiminoquinone alkaloid, tsitsikammamine C (1), displayed potent in vitro antimalarial activity with IC(50) values of 13 and 18 nM against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum, respectively. Tsitsikammamine C (1) displayed selectivity indices of >200 against HEK293 cells and inhibited both ring and trophozoite stages of the malaria parasite life cycle. Previously reported compounds makaluvamines J (2), G (3), L (4), K (5) and damirones A (6) and B (7) were also isolated from the same marine sponge (Zyzzya sp.). Compounds 2-4 displayed potent growth inhibitory activity (IC(50) < 100 nM) against both P. falciparum lines and only moderate cytotoxicity against HEK293 cells (IC(50) = 1-4 μM). Makaluvamine G (3) was not toxic to mice and suppressed parasite growth in P. berghei infected mice following subcutaneous administration at 8 mg kg(-1) day(-1).

Guiding principles for natural product drug discovery

Natural products (NPs) have historically been a fertile source of new drugs for the pharmaceutical industry. However, this once-popular approach has waned considerably over the past two decades as the high-throughput screening of megalibraries comprised mainly of molecules with non-natural (synthetic) motifs has unfolded. Contemporary high-throughput screening libraries contain molecules compliant with physicochemical profiles considered essential for downstream development. Until recently, there was no strategy that aligned NP screening with the same physicochemical profiles. An approach based on Log P has addressed these concerns and, together with advances in isolation, afforded NP leads in timelines compatible with pure compound screening. Concomitant progress related to access of biological resources has provided long-awaited legal certainty to further facilitate NP drug discovery.

Psammaplysin H, a new antimalarial bromotyrosine alkaloid from a marine sponge of the genus Pseudoceratina

Mass-directed isolation of the CH(2)Cl(2)/CH(3)OH extract from a marine sponge of the genus Pseudoceratina resulted in the purification of a new antimalarial bromotyrosine alkaloid, psammaplysin H (1), along with the previously isolated analogs psammaplysins G (2) and F (3). The structure of 1 was elucidated following 1D and 2D NMR, and MS data analysis. All compounds were tested in vitro against the 3D7 line of Plasmodium falciparum and mammalian cell lines (HEK293 and HepG2), with 1 having the most potent (IC(50) 0.41μM) and selective (>97-fold) antimalarial activity.

Ianthelliformisamines A–C, Antibacterial Bromotyrosine-Derived Metabolites from the Marine Sponge Suberea ianthelliformis

A high-throughput screening campaign using a prefractionated natural product library and an in vitro Pseudomonas aeruginosa (PAO200 strain) assay identified two antibacterial fractions derived from the marine sponge Suberea ianthelliformis. Mass-directed isolation of the CH(2)Cl(2)/CH(3)OH extract from S. ianthelliformis resulted in the purification of three new bromotyrosine-derived metabolites, ianthelliformisamines A-C (1-3), together with the known natural products aplysamine 1 (4) and araplysillin I (5). The structures of 1-3 were determined following analysis of 1D and 2D NMR and MS spectroscopic data. This is the first report of chemistry from the marine sponge S. ianthelliformis. Ianthelliformisamine A (1) showed inhibitory activity against the Gram-negative bacterium P. aeruginosa with an IC(50) value of 6.8 μM (MIC = 35 μM).

Convolutamines I and J, antitrypanosomal alkaloids from the bryozoan Amathia tortusa

Mass-directed isolation of the CH(2)Cl(2)/CH(3)OH extract from the marine bryozoan Amathia tortusa resulted in the purification of two new brominated alkaloids, convolutamines I (1) and J (2). The structures of 1 and 2 were determined following spectroscopic data analysis. Both compounds were isolated during a drug discovery program aimed at identifying new antitrypanosomal leads from a prefractionated natural product library. Compounds 1 and 2 were shown to be active toward the parasite Trypanosoma brucei brucei with IC(50) values of 1.1 and 13.7 μM, respectively. Preliminary toxicity profiling was also performed on both 1 and 2 using the human embryonic kidney cell line, HEK293. Compound 1 was shown to exhibit cytotoxicity against HEK293 with an IC(50) of 22.0 μM whilst 2 was inactive at 41.0 μM.

Analysis of Physicochemical Properties for Drugs of Natural Origin

The impact of time, therapy area, and route of administration on 13 physicochemical properties calculated for 664 drugs developed from a natural prototype was investigated. The mean values for the majority of properties sampled over five periods from pre-1900 to 2013 were found to change in a statistically significant manner. In contrast, lipophilicity and aromatic ring count remained relatively constant, suggesting that these parameters are the most important for successful prosecution of a natural product drug discovery program if the route of administration is not focused exclusively on oral availability. An examination by therapy area revealed that anti-infective agents had the most differences in physicochemical property profiles compared with other areas, particularly with respect to lipophilicity. However, when this group was removed, the variation between the mean values for lipophilicity and aromatic ring count across the remaining therapy areas was again found not to change in a meaningful manner, further highlighting the importance of these two parameters. The vast majority of drugs with a natural progenitor were formulated for either oral and/or injectable administration. Injectables were, on average, larger and more polar than drugs developed for oral, topical, and inhalation routes.