The sphingolipid metabolism pathway is vital to the growth of rapidly dividing cancer cells. All branches of this pathway involve the common metabolic precursor and central lipid, ceramide (Cer). SMS is responsible for generating SM and diacylglycerol (DAG) by transferring the phosphocholine from phosphatidylcholine onto the primary hydroxyl group of ceramides. SMS is also biologically important as it regulates the levels of ceramide and DAG as important bioactive lipids.  SMSs are present in all tissues, and SMS1 is the principal contributor for the SMS activity in most cells. Both of the isoforms share 57% of sequential identity and are conserved in mammals. Formation of Sphingomyelin is essential for cell growth and survival. In a mouse lymphoid cell line deficient in SM synthase activity halted cell growth in serum-free conditions, which could be restored by supplemental exogenous SM or heterologous expression of SMS1. SMS1 activity can be blocked by the naturally occurring anhydrophytosphingosine, jaspine B Jaspine B binds to SMS1 with high affinity due to its close structural resemblance to Cer. Jaspine B-mediated inhibition of SMS1 results in the cellular accumulation of Cer. Increased cellular Cer triggers apoptotic cell death cascades. Our hypothesis is that more potent and highly selective inhibitors of SMS1 such as novel jaspine B analogs, used alone or in combination with agents targeting these alternative Cer pathways, will prove highly efficacious in stimulating apoptotic cell death.<br/><br/>Based on SAR studies performed in B16 melanoma cells and sarcoma cells, C-2 alkyl chain with heteroatoms and with a total atom length of 17 –19 from C-4 amine exhibited a comparable IC50 to jaspine B.<br/>N, N’-dialkylated jaspine B amide analogs 1.2. will be synthesized using lactol 1.1. Under physiological conditions, these analogs are ionized (-NHR3+) mimicking covalent catalysis transition state. R1 varies from saturated C1-C11 alkyl chains and cycloalkyl motifs. N- substitutions can modulate the basicity of “N”, probing the optimum chain length required for potency, and a sterically hindered ‘N’ can minimize Cyp-450 mediated N-dealkylation phase I metabolism [10]. Lactol 1.1 will be subjected to a sequential reductive amination with R1 (C2-8, Ar, hetero-aryl) and R2 (Me, Et, Cp) substitutions followed by amidation of C-4 amine affords N, N’-dialkylated jaspine B amide analogs 1.2

Synthesis of SMS1 selective jaspine B – ceramides using reductive amination strategy

ACS Spring 2022

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