Identification of two meridianins from the crude extract of the tunicateAplidium meridianumby tandem mass spectrometry

Abstract

As part of the development of an analytical technique for the detection of meridianins and related compounds in biological fluids, a crude extract of the tunicate Aplidium meridianum was analysed using neutral loss tandem mass spectrometry. The 41 u neutral loss-EI(+) mass spectrum showed molecular ions corresponding to two previously undetected alkaloids. We report herein the isolation and structure elucidation of these alkaloids, meridianins F and G.

Variolins and Related Alkaloids

“…42 The variety of naturally occurring meridianins allowed a small investigation of structure-activity relationships (Figure 9). The unsubstituted meridianin skeleton found in meridianin G (12) was only weakly inhibitory, while a single bromine for hydrogen substitution at the 5-or 6-position of the indole ring (meridianin C (8) and D (9), respectively) resulted in considerable improvements in potency, with up to 1000-fold decreases in IC 50 observed in favorable cases. Interestingly, in meridianin F (11), the presence of two bromine atoms, at both the 5-and 6-positions, resulted in improved potency relative to meridianin G (12) but decreased potency compared to either monobrominated meridianin C (8) or D (9).…”

Meridianin derivatives as potent Dyrk1A inhibitors and neuroprotective agents

“…The selectivity of key compound over other Dyrk's (Dyrk2 and Dyrk3) was also studied. The molecular modeling studies were carried out to Meridianin C (19) and G (18) were synthesized in four steps starting from commercially available indoles 10-11 as shown in Scheme 1 23 The synthesized meridianins C and G were characterized by comparison of their spectral data with literature values. 18,19 The N-acyl and N-alkyl derivatives 26a-i and 27a-g were prepared as described earlier 24 and is depicted in Scheme 2.…”

“…The molecular modeling studies were carried out to Meridianin C (19) and G (18) were synthesized in four steps starting from commercially available indoles 10-11 as shown in Scheme 1 23 The synthesized meridianins C and G were characterized by comparison of their spectral data with literature values. 18,19 The N-acyl and N-alkyl derivatives 26a-i and 27a-g were prepared as described earlier 24 and is depicted in Scheme 2. Similarly, a library of N-sulfonyl derivatives 29a-ad were prepared from meridianins C and G. Treatment of meridianins C and G with different substituted sulfonyl chlorides 28a-t in presence of DIPEA and DMAP produced N-sulfonyl products 29a-ad in 38-87% yield (Scheme 3).…”

Alkaloids from Marine Invertebrates as Important Leads for Anticancer Drugs Discovery and Development

“…Substitution of a hydroxyl group for hydrogen at the indole position 4, as seen in meridianin A (9), resulted in smaller improvements in potency, while a bromine at position 7 and a hydroxyl group at position 4 (as seen in meridianin E (13)) resulted in the most potent compounds, with IC50 values in the low M to high nM range, depending on the target. (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) More recently, an additional series of compounds with a similar structure to the meridianins was discovered. The aplicyanin family was isolated from the Antarctic tunicate Aplidium cyaneum and consists of six variants on a core 3-(tetrahydropyrimidyl)indole structure (aplicyanins A-F, 16-21, Figure 3); these alkaloids can be considered reduced forms of the relevant meridianins and, thus, their biogenetic precursors [17].…”

“…The structures of variolin analogues are shown in Figure 2. Meridianins are a family of 3-(2-aminopyrimidine)indoles isolated from Aplidium meridianum, an ascidian from the South Atlantic [14,15] that shares some structural similarity with variolins, with the meridianins possessing a pyrimidyl-substituted indole skeleton and variolin B possessing a pyrimidyl substituted pyrido[3',2': 4,5]pyrrolo[1,2-c]pyrimidine skeleton. Moreover, the meridianin structure was identified as a promising kinase-inhibitory scaffold [16].…”