Fig 2: Proposed (A) intramolecular and (B) intermolecular electrostatic interactions (blue dashed line) for CK147 which inhibit activity towards the PSMA receptor and CHKA.

Fig 3: The modifications of CK146 via the prodrug strategy and drug delivery strategy. (A) Synthesis of CK146 (4); reaction conditions: (i) 1,14-bromotetradecane, 2-butanone, 110 °C, 3 h; (ii) Di-tert-butyl decarbonate, DMAP, DCM, RT, 16 h; (iii) MeCN, 110 °C, 72 h; (iv) TFA, MeCN, RT, 16 h; (B) Synthesis of CK145 (5) and CK147 (8); reaction conditions: (v) α-Boc-Lys (ε-Ac)-OH, EDC HCl, HOBt, DIEA, DMF, RT, 24 h; (vi) Dithiodiglycolic acid, EDC HCl, HOBt, DIPEA, DMF, RT, 72 h; (vii) TCEP, Tris-HCl, NaOH, PSMA-Maleimide (9), DMF, N2, RT, 24 h; (viii) TFA, DCM, RT, 16 h.

Fig 4: Design of two drug development strategies based on CK146. (a) ε-(Ac) Lys prodrug strategy; (b) PSMA-targeted drug delivery strategy.

Fig 5: Kaplan-Meier survival curve to show the correlation between vascular PSMA expression and overall survival in patients with HCC. HCC, hepatocellular carcinoma; PSMA, prostate-specific membrane antigen.