A practical metal-free oxidative Ugi-type three-component assembly has been achieved efficiently, employing a tertiary-amine-derived iminium ion as an imine surrogate, N-hydroxyimide as an acid surrogate, and DEAD as an oxidant. This dual-surrogate Ugi variant proceeded with a broad substrate scope and desired functional group tolerance, leading to a wide range of N-alkyl-N-acyl amino­phthalimide and N-alkyl-N-acylamino­succinimide derivatives in good isolated yields.

Human-derived in vitro models can provide high-throughput efficacy and toxicity data without a species gap in drug development. Challenges are still encountered regarding the full utilisation of massive data in clinical settings. The lack of translated methods hinders the reliable prediction of clinical outcomes. Therefore, in this study, in silico models were proposed to tackle these obstacles from in vitro to in vivo translation, and the current major cell culture methods were introduced, such as human-induced pluripotent stem cells (hiPSCs), 3D cells, organoids, and microphysiological systems (MPS). Furthermore, the role and applications of several in silico models were summarised, including the physiologically based pharmacokinetic model (PBPK), pharmacokinetic/pharmacodynamic model (PK/PD), quantitative systems pharmacology model (QSP), and virtual clinical trials. These credible translation cases will provide templates for subsequent in vitro to in vivo translation. We believe that synergising high-quality in vitro data with existing models can better guide drug development and clinical use.

Patients with cardiovascular comorbidity are less tolerant to cardiotoxic drugs and should be treated with reduced doses to prevent cardiotoxicity. However, the safe‐equivalent dose of antitumor drugs in patients with cardiovascular disease/risk is difficult to predict because they are usually excluded from clinical trials as a result of ethical considerations. In this study, a translational quantitative system pharmacology‐pharmacokinetic‐pharmacodynamic (QSP‐PK‐PD) model was developed based on preclinical study to predict the safe‐equivalence dose of doxorubicin in patients with or without cardiovascular disease. Virtual clinical trials were conducted to validate the translational QSP‐PK‐PD model. The model replicated several experimental and clinical observations: the left ventricular ejection fraction (LVEF) was reduced and the left ventricular end‐diastolic volume (LVEDV) was elevated in systolic dysfunction rats, the LVEF was preserved and LVEDV reduced in diastolic dysfunction rats, and patients with preexisting cardiovascular disease were more vulnerable to doxorubicin‐induced cardiac dysfunction than cardiovascular healthy patients. A parameter sensitivity analysis showed that doxorubicin‐induced cardiovascular dysfunction was mainly determined by the sensitivity of cardiomyocytes to cardiotoxic drugs and the baseline value of LVEDV, reflected in LVEF change percentage from the baseline. Blood pressure was the least sensitive factor affecting doxorubicin‐induced cardiotoxicity.

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