Small molecules account for the activities of 90% of drugs, with the other 10% mainly comprising large molecule biologics. But how many chemicals would it take to synthesise all small molecules? According to Martin Burke, the number is around 5000.
That figure could be crucial in helping to expedite progress in a new field of medicine called ‘molecular prosthetics’, explained Burke, who is with the Howard Hughes Medical Institute and University of Illinois at Urbana-Champaign in the US – an area that seeks to use small molecules as surrogates to restore the functions of defective proteins implicated in a host of currently untreatable diseases.
‘Artificial arms replace the function of an arm or leg that’s missing due to injury,’ Burke reported at the ACS meeting in Indianapolis in September 2013. ‘Some diseases occur because proteins in the body are missing or not working properly. Molecular prosthetics envisages treating those diseases with medicines that replace the functions of those missing proteins.’
Most current drugs work by inhibiting the functions of protein enzymes and receptors, whereas molecular prosthetics aims to treat diseases caused not by an excess but instead a deficiency of protein function, he elaborated. ‘In such cases there is no protein target to inhibit. As a result, many of these types of diseases caused by protein deficiencies have remained incurable.’
Burke’s own work has focused on a small molecule called amphotericin B, currently used to treat fungal infections. Amphotericin B inserts itself into cell membranes where it forms channels that enable the transport of ions into and out of the cell, mirroring the activity of many proteins whose function is critical in health and disease. A whole group of human diseases, sometimes called ‘channelopathies’, result from malfunction of ion channel proteins (see image), including migraine, epilepsy and cystic fibrosis.
However, making amphotericin B is a ‘Herculean task,’ Burke says. Making any small molecule can often take months or even years of laboratory work and is regarded as a major bottleneck not only for the development of molecular prosthetics, but also for new pharmaceuticals and materials.
Some years ago Burke’s team developed special building blocks – MIDA boronates – to improve the utility of the Nobel-prizewinning Suzuki-Miyaura cross-coupling reaction, to make a group of useful small molecules called polyenes (C&I, 2008, 1, 7). MIDA boronates are now available commercially and frequently employed in the hunt for new drugs.
Now, in a major breakthrough reported at the ACS meeting, and described in a patent (WO2012/149182 A2) in November 2012, Burke’s group has extrapolated this idea to produce a long sought-after automated synthesiser for small molecules – by using iterative cycles of deprotection, coupling and purification (via simple silica column chromatography) based around this one basic cross-coupling reaction to stitch together chiral small molecules in just days.
The impact of a general method for automated small molecule synthesis will be ‘extraordinary’ and will transform the study of these compounds in much the same way that DNA, peptide and oligonucleotide synthesisers have dramatically accelerated progress in other branches of medicine, Burke predicts. ‘This new platform has the potential to help shift the rate limiting step in small molecule science from synthesis to function and deliver the power of making small molecules to non-specialists.’
One recent application of this type of platform chemistry, for example, Burke explained, has been to create amphotericin B (AmB) analogues that retain antifungal activity but lack the toxicity to humans cells that has traditionally hampered usefulness. Surprisingly, the researchers discovered that analogues lacking the C2’ hydroxyl group of amphotericin B still bound to ergosterol found in yeast cells, but not to its cholesterol equivalent in human cells – believed to be the main mechanism for toxicity.
Burke’s group, meanwhile, is continuing to make progress in extending the versatility of its platform chemistry to yet other small molecules, including polycyclic molecules made by folding of the corresponding linear structures. One of the complex structures made to date, for example, is the 1,1-disubstituted olefin ratanhine, made via a novel (1-bromovinyl)-MIDA boronate building block described in a recent paper in Tetrahedron (2013, 69, 7732).
And if 5000 compounds sounds like a rather large number to make all small molecules, at the time of his ACS presentation, Burke pointed out that there were 238,541 known natural products, of which 2839 are polyenes. Around 75% of these can be made by a ‘mix and match’ process starting from just 12 chemical building blocks, he notes.
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