Figure 1. Hepatic glucose production and glucose-6-phosphatase system. Gluconeogenesis and glycogenolysis are two major processes for hepatic glucose production and both involve a common intermediate glucose-6-phosphate (G6P). G6P is finally hydrolyzed to glucose and phosphate at liver by the G6Pase complex. G6P, glucose-6-phosphate; G6Pase, glucose-6-phosphatase; Pi, Phosphate; T1, T2, T3, translocases.

Figure 2. Examples of natural and synthetic inhibitors of G6Pase. Mumbaistatin (1) is the most potent known natural inhibitor of G6P T1 with IC₅₀ of 5 nM. Kodaistatin A and chlorogenic acid (2) are also G6P T1 specific natural inhibitors. CJ-21,164 and thielavin A to P (depending on R groups) are polyphenol natural products and inhibit G6Pase complex. S4048 (3) is a synthetic analog of chlorogenic acid which shows the best potency against G6P T1 so far with IC₅₀ of 3 nM.

Figure 3. (a) Dynamic equilibrium of mumbaistatin. Diketo form (1) of mumbaistatin has an IC₅₀ of 5 nM. However, it tends to form a lactone assisted by carboxylic acid at C-2 and eventually form a spiroketal lactone (4) which possess much less potency. (b) Biosynthesis of DMAC (5) and aloesaponarin II (6) from engineered type II polyketide synthases. Octaketide synthase (act PKS) with a ketoreductase and cyclase/aromatase enzymes forms DMAC (5) and its decarboxylated compound aloesaponarin II (6) as major biosynthetic products. The southern block of the open diketo form of mumbaistatin (1) has the identical structure to DMAC (5).

Figure 4. Synthetic manipulation of DMAC. (a) Methyl protection and benzylic bromination of DMAC (b), (c) nucleophilic substitution and Suzuki coupling of monobromide of DMAC (9), (d) Wittig salt formation and Wittig reaction with DMAC.

Figure 5. Deprotection of mumbaistatin analogs. (a) Model study with trimethyl-protected DMAC (7). Saponification deprotects only methyl ester, and BBr₃ condition deprotects the methyl ester and one of the phenyl methyl ethers. (b) Deprotection of Wittig products. (c) Mechanistic interpretation of isocoumarin formation.

Figure 6. Synthesis of the analog containing salicylic acid southern block.

Figure 7. Biological activity of mumbaistatin analogs. (a) Biosynthetic and synthetic analogs of mumbaistatin and their inhibition of G6P T1. Compounds 43 and 44 are biosynthetic analogs previously reported.^{[22] and [44]} Compounds 26 and 27 are synthetic analogs with linear northern blocks. Compounds 28, 29, and 25 are synthetic analogs with aromatic northern blocks. Compound 30 is an analog containing isocoumarin moiety. Compounds 23 and 42 are analogs without oxygen species at the benzylic position. (b) Rat liver microsome assay of compound 29. (c) Effect of compound 29 on glucose output from rat hepatocytes. Cryopreserved hepatocytes were incubated and prepared for the assay as described in Section 4. Results are expressed as percent output in the presence of 25 nmol/L glucagon. Glucagon-stimulated glucose output was 0.31 ± 0.005 μmol  · 10⁶ cells⁻¹ h⁻¹.