Chemical Research on Antitumor Isoquinoline Marine Natural Products and Related Compounds

Abstract

The biologically active, naturally occurring 1,2,3,4-tetrahydroisoquinoline-quinone (THIQ) family members isolated from Actinomycetes and marine organisms have been studied thoroughly over the past five decades. Among them, marine natural products along with their reduced compounds, such as renieramycins and ecteinascidins, have attracted interest due to their fantastic structures and meager availability in nature as well as their potent antitumor profiles. As part of our search for new anticancer metabolites through the isolation and characterization of anticancer THIQ compounds from Thai marine animals, we have developed a fascinating THIQ natural product chemistry and medicinal chemistry based on knowledge of the chemistry of saframycin antibiotics as well as their isolation, characterization, transformation, partial synthesis, and total synthesis. This review mainly presents our contributions during 1999-2019 to the field of research on biologically active renieramycin along with ecteinascidin marine natural products.

Natural Products Containing the Nitrile Functional Group and Their Biological Activities

“…Renieramycins are marine alkaloids belonging to the broader saframycin family, and are classified structurally as 1,2,3,4-tetrahydroisoquinoline-quinone derivatives. 26 Of the various renieramycins isolated to date, several examples stabilised with a nitrile functionality (vide infra) have been isolated from sponges in the genera Xestospongia and Cribrochalina . Renieramycins 53 to 65 (with lettered designations) bear a nitrile (Figure 6).…”

“…The structural complexity and rarity of the natural ecteinascidins have led to the development of a semisynthetic process from another nitrile, the readily available cyanosafracin B. 26 The simple 1,2,3,4-tetrahydroisoquinoline 71 (Figure 7) was isolated from a low polar fraction of the crude extract of the KCN-pretreated Thai tunicate, Ecteinascidia thurstoni. 33 Examination of a Chinese strain of Streptomyces, sp.…”

Transformation of Renieramycin M into Renieramycins T and S by Intramolecular Photoredox Reaction of 7-Methoxy-6-methyl-1,2,3,4-tetrahydroisoquinoline-5,8-dione Derivatives

“…In the course of our exhaustive search for new antitumor natural products, we have developed syntheses leading to the elucidation of the chemistry and medicinal chemistry of fascinating 1,2,3,4-tetrahydroisoquinolinequinone (THIQ) marine natural products such as ecteinascidins ( 1 ) and renieramycins ( 2 ) on the basis of knowledge of the chemistry of saframycin antibiotics ( 3 ) including their isolation, characterization, transformation, and partial and total syntheses (Figure ). …”

Formal Synthesis of Ecteinascidin 743 via an Intramolecular Cascade Heck Reaction to Construct the Diazabicyclo[3.3.1]nonane Framework

“…ET743 exhibits strong cytostatic properties and antitumor activity, and it is currently being used for the treatment of soft-tissue sarcoma and ovarian cancer in many countries . Structure–activity relationship studies of analogues of ET743 have also been conducted for the development of novel antitumor drugs. , ET743 has a bis-tetrahydroisoquinoline skeleton as well as a 10-membered cyclic sulfide, onto which a spiro tetrahydroisoquinoline unit is substituted. These unique structural features have prompted numerous synthetic studies of ET743, leading to an expansion of the utility of a variety of reactions and to the discovery of unexpected chemical behaviors of the densely functionalized molecules. , …”