Optimization of ether and aniline based inhibitors of lactate dehydrogenase

Abstract

Lactate dehydrogenase (LDH) is a critical enzyme in the glycolytic metabolism pathway that is used by many tumor cells. Inhibitors of LDH may be expected to inhibit the metabolic processes in cancer cells and thus selectively delay or inhibit growth in transformed versus normal cells. We have previously disclosed a pyrazole-based series of potent LDH inhibitors with long residence times on the enzyme. Here, we report the elaboration of a new subseries of LDH inhibitors based on those leads. These new compounds potently inhibit both LDHA and LDHB enzymes, and inhibit lactate production in cancer cell lines.

Keywords: Cancer metabolism; LDH inhibitor; Medicinal chemistry; Structure activity relationships.

Figure 1.

Previously reported pyrazole-based LDH inhibitors.^,

Figure 2.

X-ray co-crystal structure of 1a bound to LDHA (PDB code 5W8L). Oxygen atoms are shown in red, nitrogens in blue. Lipophilic space is highlighted by a blue oval. Surface representation of Lys105 omitted for clarity.

Scheme 1.

Preparation of 5-H pyrazole analogs. Reagents and conditions: (a) C₂H₅OCHO, NaH; (b) hydrazine, ethanol, 92 % (two steps); (c) NBS, DMF, 70 %; (d) ethyl 2-bromothiazole-4-carboxylate, K₂CO₃, DMSO, 73%; (e) BBr₃, DCM, 60 %; (f) K₂CO₃, DMF; (g) 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane), PdCl₂(dppf), 1,4-dioxane; (h) Pd(PPh₃)₄, K₂CO₃, dioxane, water; (i) 1 M LiOH, THF, methanol.

Scheme 2.

Preparation of 5-methylene cyclopropyl pyrazole analogs. Reagents and conditions: (a) R¹Br, K₂CO₃, DMF, 100–160 °C; b) R¹OH, PPh₃, di-t-butyl diazocarboxylate THF, 0 °C. 95%; c) R¹B(OH)₂, Cu(OAc)₂, pyridine, DCM; (d) MgBr₂-OEt₂, DCM, DIPEA; e) Cs₂CO₃, KI, DMSO; (f) pyrrolidine, EtOH, pTSA 90°C; (g) LiOH or NaOH, dioxane, MeOH, water; (h) R⁵NC, PdCl₂(Ph₃P)₂, CsF, DMSO, water; (i) NH₂R⁵, K₃PO₄, Pd(P(tBu)₃)₂, DMA, 53 %; (j) HN(R⁵)₂, Mo(CO)₆, Pd(OAc)₂, T-BINAP, Cs₂CO₃, MeCN, toluene.