Simon F. Campbell

A novel multiple-stage antimalarial agent that inhibits protein synthesis

There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.

The geometries of interacting arginine‐carboxyls in proteins

The geometries are reported for interacting arginine‐carboxyl pairs obtained from 37 high resolution protein structures solved to a resolution of 2.0 Å or better. The closest interatomic distance between the guanidinium and carboxyl is less than 4.2 Å for 74 arginine and carboxyl groups, with the majority of these lying within hydrogen‐bonding distance (2.6–3.0 Å). Interacting pairs have been transformed into a common orientation, and arginine‐carboxyl, and carboxyl‐arginine geometries have been calculated. This has been defined in terms of the spherical polar angles Tθ, Tϕ, and the angle P, between the guanidinium and carboxyl planes. Results show a clear preference for the guanidinium and carboxyl groups to be approximately coplanar, and for the carboxyl oxygens to hydrogen bond with the guanidinium nitrogens. Single nitrogen‐single oxygen is the most common type of interaction, however twin nitrogen‐twin oxygen interactions also occur frequently. The majority of these occur between the carboxyl oxygens and the NH1 and NE atoms of the arginine. and are only rarely observed for NH1 and NH2. The information presented may be of use in the modelling of arginine‐carboxyl interactions within proteins.

Studies related to the synthesis of pederin. Part 2. Synthesis of pederol dibenzoate and benzoylpedamide.

Abstract Syntheses of the ring B fragments (+)-pederol dibenzoate (2) and (±)-benzoylpedamide (3) of the insect toxin pederin (1) are described. An intramolecular directed aldol condensation was used to construct the tetrahydropyran ring in (+)-pederol dibenzoate (2). Better stereocontrol in the synthesis of (±)-benzoylpedamide (3) was achieved in which the stereochemistry at C-11 was introduced by a conjugate addition of TMSCN to the dihydropyranone (31). The synthesis of (±)-pederin from (±)-(3) and the ring A. fragment (±)-benzoylselenopederic acid (38) is described.

Studies related to the synthesis of (±)-pederin. part 1. Synthesis of ethyl pederate and benzoylselenopederic acid

Abstract The first in a series of 2 papers on the synthesis of the insect toxin pederin (1) begins with a discussion of syntheses of the ring A fragments (±)-ethyl pederate (2) and (±)-benzoylselenopederic acid (4). A silicon-mediated intramolecular cyclisation of a chloroformate onto an allyl silane (11) was used to introduce the ring A methylene group at C-4 in ethyl pederate. Conjugate addition of phenylselenomethyl-lithium to the α,β-unsaturated lactone (19) was a key step in the construction of (4).

Long-acting dihydropyridine calcium antagonists. 9. structure activity relationships around amlodipine

Abstract The preparation of a range of 1,4-dihydropyridine analogues of amlodipine has been undertaken and their calcium antagonist activities on rat aorta have been evaluated. Increasing the size of the C5 ester group dramatically reduces calcium antagonist activity, a trend which would be compatible with the carbonyl group of that ester binding to the DHP receptor. Amlodipine analogues with extended C3 ester substituents also have lower potency than amlodipine, possibly because of disruption of a favourable interaction between the protonated amino group on the 2-substituent and the DHP receptor. Replacement of the 6-methyl substituent in amlodipine by alkoxyalkyl groups or electron-withdrawing groups is also detrimental to calcium antagonist activity.

A directed aldol approach to (+)-milbemycin β3

Key steps in a total synthesis of (+)-milbemycin β3are the construction of the 1,7-dioxaspiro[5.5]undecane (10) by a Lewis acid-catalysed intramolecular directed aldol reaction and the use of sulphone-based olefination reactions for the construction of the double bonds at C(10)–C(11) and C(14)–C(15)

The 3,4-dihydro-2H-pyran approach to (+)-milbemycin β3. Part 1. An alternative synthesis of (2S,4S,6R,8R,9S)-2-formylmethyl-4-(dimethyl-t-butylsilyloxy)-8,9-dimethyl-1,7-dioxaspiro[5.5]undecane

A more efficient synthesis of the title compound (12), previously used in a total synthesis of (+)-milbemycin β3(2), is described. The key step in the sequence involves a nucleophilic cleavage of the oxirane (33) by the organocuprate (28) derived from metallation of (2R,3S)-2,3-dimethyl-3,4-dihydro-2H-pyran (26).

A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance.

K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.

The total synthesis of (±)-pederin

The conjugate addition of phenylselenomethyl-lithium to the α,β-unsaturated lactone (4) was a key step in a short synthesis of (±)-benzoylselenopederic acid (2); union of (2) and (±)-benzoylpedamide (3) by a modification of known procedures gave (±)-pederin (1).

A synthesis of (+)-milbemycin β3. The 3,4-dihydro-2H-pyran approach

Nucleophilic scission of oxirane (8) by vinyl alanate (4) and oxirane (11) by metallated 3,4-dihydro-2H-pyran (15) were key steps in the synthesis of (+)-milbemycin β3(1).