**1. Introduction**

The hemostatic system, consisting of the coagulation and fibrinolytic systems, is a vital physiological function in inhibiting hemorrhage and accelerating wound healing [1,2]. Fibrinolysis is regulated by plasminogen and activated by physiologic plasminogen activators: tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). Meanwhile, the level of activated plasmin could be inhibited through the block of plasminogen activation by several specific molecules [3,4]. However, various clinical cases indicated that hereditary or acquired factors would enhance or weaken fibrinolytic systems, causing the disorder between the coagulation and fibrinolytic systems, which led to hemorrhage or thrombosis. Compared with a hemorrhage, thrombus formation develops much more gradually and imperceptibly, leading many patients' deaths [5]. Current drugs on thrombosis include aspirin, ticlopidine, warfarin, and heparin; however, the risk of bleeding is a concern [6]. Therefore, small molecules, with different mechanisms of fibrinolysis action, are desired for new antithrombotics and thrombolytics.

**Citation:** Hang, S.; Chen, H.; Wu, W.; Wang, S.; Fang, Y.; Sheng, R.; Tu, Q.; Guo, R. Progress in Isoindolone Alkaloid Derivatives from Marine Microorganism: Pharmacology, Preparation, and Mechanism. *Mar. Drugs* **2022**, *20*, 405. https://doi.org/ 10.3390/md20060405

Academic Editors: Wenhan Lin, Guoqiang Li and Jing Xu

Received: 28 April 2022 Accepted: 17 June 2022 Published: 20 June 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Natural products, historically, possess various bioactivities for the treatment of human diseases [7–12]. Marine products, due to the unique marine environments, provide special structures of compounds differing from terrestrial ones. Up to now, over 28,175 chemical entities have been identified, with hundreds of new compounds discovered every year [13]. Numerous marine molecules have been approved for clinical treatments, such as anticancer cytarabine and analgesic ziconotide [14–16].

In 1996, Kohyama et al. isolated SMTP-1 from fungi *Stachybotrys microspora* IFO 30018, with 20–30% higher plasminogen-fibrin binding action than staplabin, indicating the potential for thrombolysis therapy [17–19]. Staplabin, a triprenyl phenol, was the basic core of the SMTP family, and SMTP-1, as well as other congeners, were variants of staplabin (Figure 1) [17,20]. Then, a series of congeners, containing a tricyclic γ-lactam moiety, a geranylmethyl side-chain, and an N-linked side-chain, were isolated and showed plasminogen activation [21]. Compound **1** (Figure 2), with two staplabin cores bridged by ornithine, could increase urokinase-catalyzed plasminogen activation, fibrin binding of plasminogen, and fibrinolysis mediated by urokinase and plasminogen [20]. Meanwhile, it showed excellent clot clearance activity in vivo [22,23]. In a rat pulmonary embolism model, compound **1** (5 mg/kg) enhanced, by three-fold, the clot clearance rate above the spontaneous clearance group. Moreover, clot clearance of compound **1** was enhanced, further, in combination with u-PA [23].

**Figure 1.** Structures of staplabin and SMTP-1.

At present, more than 60 congeners of staplabin have been isolated, which not only performed fibrinolysis activity but also exhibited various effects, such as anti-inflammatory, neuroprotection, and anti-cancer properties [1]. Other modified derivatives and structure– function relationships of compound **1** have also been studied. Scientists also confirmed the absolute configuration and preparation methods of congeners and derivatives, which shared similar absolute configuration (8S, 9S) and a staplabin core. Meanwhile, most monomeric analogues could be obtained by replacing the ornthine with non-basic amino acids or simple amines [24,25]. Herein, we focused on the diverse biological activities of compound **1**, which is a congener of staplabin (Figure 2).

**Figure 2.** *Cont*.

**Figure 2.** *Cont*.

**Figure 2.** Structures of congeners and derivatives of staplabin.
