Serine hydroxymethyltransferase (SHMT) is a central enzyme in the metabolic reprogramming of cancer cells, providing activated one-carbon units in the serine-glycine one-carbon metabolism. Previous studies demonstrated that the cytoplasmic isoform of SHMT (SHMT1) plays a relevant role in lung cancer. SHMT1 is overexpressed in lung cancer patients and NSCLC cell lines. Moreover, SHMT1 is required to maintain DNA integrity. Depletion in lung cancer cell lines causes cell cycle arrest and uracil accumulation and ultimately leads to apoptosis. We found that a pyrazolopyran compound, namely 2.12, preferentially inhibits SHMT1 compared to the mitochondrial counterpart SHMT2. Computational and crystallographic approaches suggest binding at the active site of SHMT1 and a competitive inhibition mechanism. A radio isotopic activity assay shows that inhibition of SHMT by 2.12 also occurs in living cells. Moreover, administration of 2.12 in A549 and H1299 lung cancer cell lines causes apoptosis at LD50 34 μM and rescue experiments underlined selectivity towards SHMT1. These data not only further highlight the relevance of the cytoplasmic isoform SHMT1 in lung cancer but, more importantly, demonstrate that, at least in vitro, it is possible to find selective inhibitors against one specific isoform of SHMT, a key target in metabolic reprogramming of many cancer types.

A fully enzymatic asymmetric synthesis of substituted tetrahydroisoquinolines was achieved in two steps starting from dopamine and a set of amine substrates by coupling the activity of a plant diamine oxidase with the recombinant norcoclaurine synthase enzyme from Thalictrum flavum. In the first step, a variety of aliphatic and aromatic amines of general interest as pharmaceutical building blocks were transformed into the corresponding aldehydes by the broad specificity of diamine oxidase enzyme from Lathyrus cicera. In the second step, the stereoselectivity of the norcoclaurine synthase catalyzed reaction to yield (S)‐configured tetrahydroisoquinoline products was exploited by mixing the aldehyde obtained in the first step with dopamine, the committed substrate for the Pictet‐Spengler reaction. The reactions were carried out in aqueous buffer and the products thus obtained were extracted and characterized by chiral GC/MS. Enantiomeric excess > 99% were obtained for all substrates investigated. The method provided a set of novel tetrahydroisoquinolines with potentially interesting pharmacological profiles.

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