Investigating the anti-cancer potential of pyrimethamine analogues through a modern chemical biology lens.

Pharmacological inhibition of dihydrofolate reductase (DHFR) is an established approach for treating a variety of human diseases, including foreign infections and cancer. However, treatment with classic DHFR inhibitors, such as methotrexate (MTX), are associated with negative side-effects and resistance mechanisms that have prompted the search for alternatives. The DHFR inhibitor pyrimethamine (Pyr) has compelling anti-cancer activity in in vivo models, but lacks potency compared to MTX, thereby requiring higher concentrations to induce therapeutic responses.

Cycloguanil and Analogues Potently Target DHFR in Cancer Cells to Elicit Anti-Cancer Activity.

Dihydrofolate reductase (DHFR) is an established anti-cancer drug target whose inhibition disrupts folate metabolism and STAT3-dependent gene expression. Cycloguanil was proposed as a DHFR inhibitor in the 1950s and is the active metabolite of clinically approved DHFR inhibitor Proguanil. The Cycloguanil scaffold was explored to generate potential cancer therapies in the 1970s.

The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase.

Cancer is often characterized by aberrant gene expression patterns caused by the inappropriate activation of transcription factors. Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional regulator of many protumorigenic processes and is persistently activated in many types of human cancer. However, like many transcription factors, STAT3 has proven difficult to target clinically.

Clionamines stimulate autophagy, inhibit Mycobacterium tuberculosis survival in macrophages, and target Pik1.

The pathogen Mycobacterium tuberculosis (Mtb) evades the innate immune system by interfering with autophagy and phagosomal maturation in macrophages, and, as a result, small molecule stimulation of autophagy represents a host-directed therapeutics (HDTs) approach for treatment of tuberculosis (TB). Here we show the marine natural product clionamines activate autophagy and inhibit Mtb survival in macrophages. A yeast chemical-genetics approach identified Pik1 as target protein of the clionamines.

Alkenes from β-lithiooxyphosphonium ylides generated by trapping α-lithiated terminal epoxides with triphenylphosphine.

Terminal epoxides undergo lithium 2,2,6,6-tetramethylpiperidide-induced α-lithiation and subsequent interception with Ph(3)P to provide a new and direct entry to β-lithiooxyphosphonium ylides. The intermediacy of such an ylide is demonstrated by representative alkene-forming reactions with chloromethyl pivalate, benzaldehyde and CD(3)OD, giving a Z-allylic pivalate, a conjugated E-allylic alcohol and a partially deuterated terminal alkene, respectively, in modest yields.

Convergent synthesis of conjugated 1,2-disubstituted E-allylic alcohols from two aldehydes and methylenetriphenylphosphorane.

β-Lithiooxyphosphonium ylides, made in situ from an aldehyde and methylenetriphenylphosphorane, react with a second aldehyde to form E-allylic alcohols. α-Branching and α,β-unsaturation in the second aldehyde, together with the lack of further substitution on the phosphorane carbon play important roles in selectivity. A range of these aldehydes, in addition to aromatic aldehydes as the second aldehyde also provided synthetically useful access to E-allylic alcohols.