New Selective Cytotoxic Diterpenylquinones and Diterpenylhydroquinones

Abstract

A new series of diterpenylquinone/hydroquinones has been prepared by Diels-Alder cycloaddition between three labdanic diterpenoids (myrceocommunic acid, methyl myrceocommunate, and myrceocommunyl acetate) and p-benzoquinone or 1,4-naphthoquinone. Influences of the quinone/hydroquinone fragment and other structural features, such as the different functionalities in the terpenic core, are considered in relation to the cytotoxicity toward neoplastic cells and the selectivity of these diterpenylnaphthoquinones/hydroquinones and anthraquinones. Several compounds showed IC50 values under the micromolar level, and four of these derivatives were evaluated at the NCI screening panel. The results showed an important selectivity toward renal cancer lines, identifying these compounds as a very promising group of antineoplastics.

Synthetic Strategies to Terpene Quinones/Hydroquinones

“…This has sparked interest in the chemical composition and cytotoxicity of a large number of marine species that contain metabolites with hybrid structures between terpenes and quinones/hydroquinones [76,140,141,146,147,148,149,150]. …”

Synthesis and Evaluation as Antitumor Agents of 1,4‐Naphthohydroquinone Derivatives Conjugated with Amino Acids and Purines

“…This would show the relevance of the planar naphthalenic group for the cytotoxic–antineoplastic activity, probably due to which it would allow a better intercalating association when they act as non‐covalent binders of DNA . In spite of the fact that the amino acid moiety does not significantly modify the bioactivity previously reported for naphthohydroquinones , it is interesting to note that the GI 50 values of compounds 4a – 8a against MCF‐7 breast cancer cells are very close to that of the standard drug doxorubicin and even slightly better for the phenylalanine derivative 6a . Furthermore, compounds 4a – 8a are more cytotoxic than several conjugates reported in the literature such as platinum complexes of enantiomerically pure α‐trifluoromethyl alanine , 1,4‐bis(2‐aminoethylamino)anthraquinone–, ametantrone–, and mitoxantrone–amino acid conjugates and more than naphthalimide–leucine conjugates against A‐549 and/or MCF‐7 cells. In the group of purine–naphthohydroquinone conjugates 10 – 13 , the fully aromatized compounds 10a – 13a (GI 50 2.9–8.7 μM) also showed higher cytotoxicity than the corresponding 5,8‐dihydro‐ ( 10b – 13b ) or 5,6,7,8‐tetrahydro‐ ( 10c – 13c ) derivatives against A‐549 or HT‐29 cultured cells.…”

“…In previous works, we reported on the syntheses and cytotoxicity evaluation for a number of prenylnaphthoquinones (hydroquinones) and derivatives obtained through Diels–Alder cycloaddition from myrcene and 1,2‐ or 1,4‐benzoquinones. Those previous series of compounds displayed cytotoxicity GI 50 values in the micromolar or lower range against several neoplastic cell lines and, in general, resulted more potent than avarol and avarone (3–6 μM), two meroterpenoids of marine origin, and taken as comparative references in our studies .…”

Bioactive Prenyl- and Terpenyl-Quinones/Hydroquinones of Marine Origin †

“…Myrcene is commercially available, and myrceocommunic acid can be easily isolated in enough amount from the berries of Juniperus oxycedrus (Fam. Cupressaceae) [ 167 ].…”

“…The cycloadducts, either from myrcene ( Scheme 1 ) or from myrceocommunic acid ( Scheme 2 ), were stabilized as their acetates followed by aromatization yielding acetylated naphthohydroquinone (NHQ) derivatives [ 167 , 168 ]. Direct oxidation of the cycloadducts led to the corresponding 1,4-NQ derivatives.…”