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36 new compounds with the typical skeleton of 4-anilino-5-vinyl/ethynyl pyrimidine, 4-anilino-3-cyano-5-vinyl/ethynyl/phenyl pyridine, and m-amino-N-phenylbenzamide, are designed, synthesized and selectively tested on EGFR, ErbB-2 kinases, and A-549, HL60 cells growth inhibition. Results from the bioactivity and chemical structures yield preliminary structure-activity relationships (SARs). The most potent 5-ethynylpyrimidine derivative 20a has an IC50 value of 45 nM to EGFR kinase. Several compounds of other series also show IC50 values

Macrocycles are found widely in nature where they fulfill numerous specific functions. However they have been generally underexploited as drug molecules, as they are larger than more conventional ‘Rule of 5’ compliant molecules and their synthesis and screening has been considered a challenge. Consequently most pharmaceutical companies have very few macrocycles in their screening files, and yet these compounds can have potent and selective pharmacological activity, and exhibit drug-like properties such as cell membrane permeability and oral bioavailability. To permit the further investigation of macrocyclic drugs, several groups have developed diverse methods for the rapid synthesis and screening of macrocyclic libraries.

5-(2′-Alkoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-ones, and in particular our preferred compound, sildenafil (VIAGRATM), discovered through a rational drug design programme, are potent and selective inhibitors of the type 5 cGMP phosphodiesterase from both rabbit platelets and human corpus cavernosum. Sildenafil is currently in the clinic for the oral treatment of male erectile dysfunction.

Parallel compound synthesis enables large numbers of individual compounds to be prepared simultaneously using semiautomated techniques. This fast and efficient methodology has an important role to play in accelerating lead optimisation and hence the whole drug discovery process. The potential of this strategy to rapidly optimise chemical leads and provide structure-activity relationship (SAR) information was demonstrated in two therapeutic areas, antiviral agents (herpes simplex virus), and neurokinin-2 receptor antagonists.

Radical cyclisation of sp 3 carbon-centred radicals onto imines and hydrazones provides a new method for the synthesis of 5- and 6-membered ring nitrogen heterocycles. Cyclisation onto the electrophilic carbon of the C=N group and 5- exo stereoelectronic selectivity are the dominating mechanistic parameters. The C-centred radical intermediates were generated from benzeneselenyl precursors using Bu 3 SnH.

A combinatorial library of 30,752 compounds has been synthesised from a set of 32 natural and unnatural amino acids. The library was designed to include the known endothelin antagonist, FR-139,317, as a positive control, and this and a number of close analogues were shown to be the most potent compounds. Thus, combinatorial libraries may be used both to discover leads and rapidly explore SAR. A combinatorial library of 30,752 compounds has been synthesised from a set of 32 natural and unnatural amino acids. The library was designed to include the known endothelin antagonist, FR-139,317, as a positive control, and this and a number of close analogues were shown to be the most potent compounds. Thus, combinatorial libraries may be used both to discover leads and rapidly explore SAR.

The regioselectivity of intramolecular addition of sp3 carbon-centred radicals onto CN double bonds of imines and hydrazones is influenced by the position and polarisation of the CN bond.

Reaction of a number of 1,6-diene or enyne systems with TolSO 2 SePh, under free radical conditions, results in selenosulfonylation with concomitant CC bond formation, to give cyclised alkyl or vinyl sulfones containing the synthetically useful phenylselenyl functionality. Similar cyclisations are possible by using Ph 2 PH in place of TolSO 2 SePh, resulting in the formation of cyclic phosphine or vinyl phosphine products, although in these reactions the diene substrates give rather modest yields.

Reaction of diphenylphosphine with suitable 1,6-diene or enyne systems, under free radical conditions, results in addition of a phosphorus-centred radical and cyclisation to form substituted phosphines and vinyl phosphines respectively.

Reaction of a number of 1,6-diene or enyne systems with TolSO 2 SePh, under free radical condition, results in selenosulphonylation with concommitant CC bond formation, to give cyclised alkyl or vinyl sulphones containing the synthetically useful phenylselenyl functionality.

A variety of spiroether products, including one bis-spiro compound, are available via a simple radical cyclisation route.

A search for potent inhibitors of EC 3.4.24.11, an enzyme which is found most abundantly in the kidney and which degrades atrial natriuretic factor, has led to the identification of UK-69,578. Structure-activity studies starting from substituted N-carboxymethyl dipeptide inhibitors resulted in the introduction of a cyclo-alkane P1' residue and in the replacement of the aza-link between P1 and P1' residues by a methylene group, with a net ten-fold potency gain. UK-69,578 increases endogenous ANF levels and produces natriuretic and diuretic responses intravenously in mice.

The SE2′ reactions of 1 and 2 with a range of electrophiles are predominantly anti in the allylsilane portion of the molecule, but this is offset, to a greater or lesser extent, by axial or equatorial preferences in the ring system.

The stereospecifically anti synthesis of allyl- and allenyl-silanes by the reaction of a silylcuprate reagent with allyl and propargyl acetates is described. The S E 2′ reactions of these silanes with various electrophiles are shown to proceed with predominantly anti stereoselectivity, offset to a greater or lesser extent by other steric factors.

The use of radical cyclisations allows direct access to a family of azaspirocyclic ketones, including compounds having the azaspiro[4.4]nonane, and azaspiro[5.5]undecane structures which are found in the alkaloids cephalotaxine and histrionicotoxin.

Alcohols bearing suitable chains for radical initiation are smoothly condensed with cyclic β-diketones to afford systems which undergo radical cyclisation to give various spiroether products.

The tertiary allylic acetates (1–4) and the propargylic acetates (14 and 15) react with our silyl-cuprate reagent (5) to give, in a cleanly anti manner, the stereodefined allylsilanes (6 and 7) and allenylsilanes (16 and 17).

A stereospecific synthesis of allylsilanes and their stereospecific reaction with peracid are used to prepare the endo-prop-1-enylnorbornenol (6), a substrate for an oxy-Cope rearrangement leading eventually to dihydronepetalactone (10) with complete stereocontrol.