Synthesis of avaranes and their application in the development of anticancer drugs

Abstract

The application belongs to the field of organic chemical synthesis and medicinal chemistry, and particularly relates to the field of avarane type polycyclic heteroterpene compounds, and discloses that a 6 / 6 fused dienone tertiary alcohol is converted into a spiro[4.5]ene dienone skeleton through a rare stereospecific 1,2-alkyl migration reaction, de-OEt-1'-septosones B and C, 1'-septosones B and C and spiroetherones A and B are synthesized, and the structures of spiroetherones A and B are modified. Meanwhile, biological activity tests on the synthetic intermediates find that two new compounds exhibit significant anti-cancer activity on Hep G2, MV-4-11 and MOLT-4 cell lines, and IC epi values are as low as 2.1 μM. The application provides a new way and compound basis for the research and application of related heteroterpene compounds. epi values are as low as 2.1 μM. The application provides a new way and compound basis for the research and application of related heteroterpene compounds. 50 values are as low as 2.1 μM. The application provides a new way and compound basis for the research and application of related heteroterpene compounds.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of total synthesis of polycyclic avarane-type terpenoids, in particular to the total synthesis of de-OEt-1'- epi -septosones B and C, 1'- epi -septosones B and C, and the modification of spiroetherones A and B original structure, and the discovery of new compounds with significant anti-cancer activity. BACKGROUND

[0002] Polycyclic avarane-type sesquiterpenoid quinones / hydroquinones (SQs / SHQs) are an important class of terpenoids, which bridge sesquiterpene units and quinone / hydroquinone units through one or more carbon-carbon bonds, forming complex polycyclic skeletons (such as 6 / 6 / 6 / 6 tetramer, 6 / 6 / 5 / 6 tetramer, [3.3.1] bridged ring, and spiro[4.5] ring, etc.), with more complex structures than the parent avarane-type terpenoids (avarol, neoavarol, avarone and neoavarone). As of December 2024, about 30 polycyclic avarane-type SQs / SHQs have been discovered from marine sponges, which can be divided into different subclasses according to the connection mode. In addition, such compounds have also attracted attention due to their significant biological activities such as anti-tumor, antibacterial, anti-inflammatory, etc.

[0003] Polycyclic sesquiterpenoid quinones septosones B and C are three very rare heteroterpene natural products with polycyclic structure isolated from the marine sponge Dysidea septosa in the Xisha Islands of the South China Sea by Professor Lin Houwen's research group of Shanghai Jiaotong University in 2019. Structurally, as shown in the figure, septosones B and C share a common 6 / 6 / 5 / 6 tetramer skeleton, which contains a rare spiro[4.5]decane skeleton, with a sesquiterpene fragment and a quinone fragment connected by two carbon-carbon bonds, and six consecutive stereocenters in the molecule, of which three are quaternary carbon centers. The difference between septosones B and C lies in the position of the double bond in the sesquiterpene fragment. In addition, septosone C shows certain anti-inflammatory activity, with an IC 50 value of 27.2 μM.

[0004] Polycyclic sesquiterpene naphthoquinone spiroetherones A and B were also isolated and identified by Professor Lin Houwen's research group. They are two very rare polycyclic sesquiterpene naphthoquinone heteroterpene natural products with spiro ring structure, which were isolated from the marine sponge Dysidea etheria in the Xisha Islands of the South China Sea in 2020. As shown in the figure, spiroetherones A and B have an unprecedented fused five-ring 6 / 6 / 5 / 6 / 6 skeleton, which contains a spiro[4.5]decane structure, and the sesquiterpene fragment is connected to the quinone fragment by two carbon-carbon bonds, and there are six consecutive stereocenters in the molecule, of which three are quaternary carbon centers. The difference between polycyclic sesquiterpene naphthoquinone spiroetherones A and B lies in the position of the double bond in the sesquiterpene fragment. The difference between them and the aforementioned septosones B and C is that the former is a sesquiterpene naphthoquinone and the latter is a sesquiterpene benzoquinone. It is worth noting that the spiro ring direction of spiroetherones A and B is opposite to that of septosones B and C. Due to their diverse connection modes and oxidation states, polycyclic avarane-type SQs / SHQs have attracted widespread attention in the synthetic community, and several research teams have achieved the synthesis of some related compounds. SUMMARY

[0005] The purpose of the present application is to realize the de-OEt-1'- epi -septosones B and C, the total synthesis of 1'- epi -septosones B and C and the modification of the original structure of spiroetherones A and B, and to find new compounds with significant anti-cancer activity, providing a new way and compound basis for the research and application of related terpenoid compounds.

[0006] Technical scheme: The total synthesis of de-OEt-1'- epi -septosones B and C:

[0007] dysideanone G generates dysideanone E under photooxidation conditions (RB / O2) with an 85% yield. Under acidic conditions, dysideanone E undergoes hemipinanol rearrangement (90% yield) to generate de-OEt-1'- epi -septosone B, and the single crystal structure confirms that it is a C1'epimer of natural septosone B.

[0008] dysideanone G under oxidative conditions (PIFA) to generate dysideanone A in 66% yield. Under acidic conditions, dysideanone A undergoes a hemi pinacol rearrangement (81% yield) to generate de-OEt-1'- epi -septosone C.

[0009] 1'- epi -septosones B and C:

[0010] The unprotected Wieland-Miescher ketone derivative 27 undergoes a highly chemoselective, regioselective, site-selective and diastereoselective alkylation reaction with benzyl bromide 28 in the presence of t -BuOK to generate diketone 29 in 82% yield.

[0011] Diketone 29 under acidic conditions (p-toluenesulfonic acid) selectively forms a ketal with ethylene glycol (88% yield) at the less hindered C4 carbonyl group to generate monoketone 30.

[0012] Wittig reagent to generate an exocyclic olefin (96% yield), and acid hydrolysis of the ketal (3 M HC1) liberates the C4 carbonyl group to give monoketone 31 (94% yield).

[0013] Monoketone 31 undergoes selective reduction of the exocyclic olefin (89% yield, 1.2:1 diastereoselectivity) using Wilkinson's catalyst [RhCl(PPh3)3] in homogeneous phase, followed by an AIBN / n-Bu3SnH initiated intramolecular radical cyclization to construct the 6 / 6 / 6 / 6 fused tetracyclic skeleton to give ketone 33 (structure confirmed by single crystal X-ray diffraction) in 81% yield.

[0014] Wittig reagent to generate an exocyclic olefin 34, n -BuSLi to remove the methoxy protecting group (75% yield) to give 4'-OEt-dysideanone G.

[0015] 4'-OEt-dysideanone G under photooxidative conditions (RB / O2) to generate 4'-OEt-dysideanone E in 55% yield. Under the same acidic conditions, 4'-OEt-dysideanone E undergoes a hemi pinacol rearrangement (45% yield) to generate 1'- epi -septosone B, whose single crystal structure confirms it to be the C1' epimer of natural septosone B.

[0016] To synthesize 1'- epi-septosone C, via MHAT condition [Co(Salen t -Bu, t [-Bu)Cl,PhSiH3] enables olefin migration of 4'-OEt-dysideanone G (93% yield to 4'-OEt-dysideanone F), followed by oxidation of 4'-OEt-dysideanone F with Pd(OAc)4 / AcOH to give ester 38 (75% yield). Deacetylation and rearrangement under basic conditions (K2CO3 / EtOH) yield 1'- epi -septosone C, whose single-crystal structure confirms that the spiro ring direction is opposite to that of septosone C.

[0017] Total synthesis and correction of the original structures of Spiroetherones A and B:

[0018] With unprotected Wieland-Miescher ketone derivative 27 and naphthylbenzyl bromide 39 in t A highly chemi, regio, site and diastereoselective alkylation reaction occurs under BuOK conditions, yielding diketone 40 in 75% yield.

[0019] Under acidic conditions (p-toluenesulfonic acid), the less sterically hindered C4 carbonyl group of diketone 40 selectively forms a ketal with ethylene glycol (89% yield), generating monoketone 41.

[0020] The C8 ketone of monoketone 41 was olefinized with Wittig reagent (90% yield) to generate an exocyclic olefin, and the C4 carbonyl group was released by acid hydrolysis of the ketal (3M HCl) to give monoketone 42 (95% yield).

[0021] Monoketone 42 was homogeneously hydrogenated and selectively reduced to exocyclic olefins via Wilkinson catalyst [RhCl(PPh3)3] (91% yield, 1.3:1 diastereoselectivity), followed by AIBN / n Intramolecular radical cyclization initiated by -Bu3SnH was used to construct a 6 / 6 / 6 / 6 fused tetracyclic framework, yielding monoketone 45 in 82% yield (structure confirmed by single-crystal X-ray diffraction).

[0022] Monoketone 45 was olefinically annealed with Wittig reagent (96% yield) to regenerate exocyclic olefin 46. n -BuSLi demethylation protecting group (91% yield) yields naphthol 47.

[0023] Naphthol 47 was generated in 55% yield under photo-oxidation condition (RB / O2) as a tertiary alcohol 48. Under the same acidic condition, the hemi-pinacol rearrangement of the tertiary alcohol 48 occurred to generate the originally assigned spiroetherone A in 45% yield. However, the spectral data of the synthetic product spiroetherone A did not match the natural product, and its single crystal structure confirmed that it was the C1' epimer of the natural spiroetherone A.

[0024] To synthesize spiroetherone B, olefination of spiroetherone A was achieved by MHAT condition [Co(Salen t -Bu, t -Bu)Cl, PhSiH3] to give spiroetherone B in 91% yield. By comparative analysis, the structure of the natural product was revised as 49 and 50.

[0025] Evaluation of anticancer activity of synthetic intermediates: The screening of anticancer activity of 25 intermediates found that compounds 29 and 33 significantly inhibited the proliferation of Hep G2, MV-4-11 and MOLT-4 cells at a concentration of 20 μM. Further determination of IC 50 values showed that 33 had IC 50 values of 7.3, 2.1 and 2.7 μM for the three cell lines, respectively, showing the potential of anticancer lead compounds.

[0026] Beneficial effects: The present application realizes the total synthesis of de-OEt-1'- epi -septosones B / C, 1'- epi -septosones B / C and spiroetherones A / B through the rare 1,2-alkyl migration reaction, and revises the original structures of spiroetherones A and B. The key precursors are efficiently constructed through high-selective alkylation of Wieland-Miescher ketone and radical cyclization. At the same time, the activity evaluation found two new compounds with significant anticancer activity (IC 50 as low as 2.1 μM), providing an important compound basis and research direction for the research and potential drug development of related heteroterpene compounds. The related structure-activity relationship and mechanism of action are being studied, and it is expected to further expand its application value. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 Structure of polycyclic avarane-type sesquiterpene quinone / hydroquinone and its connection mode

[0028] Figure 2Structures of septosones B and C and spiroetherones A and B

[0029] Figure 3 Investigation of the unusual spiro[4.5]decane scaffold by rare semifarnesol rearrangements

[0030] Figure 4 Synthesis of 4'-OEt-dysideanone G

[0031] Figure 5 Synthesis of 1'-epi-septosones B and C

[0032] Figure 6 Synthesis of the originally designed spiroetherones A and B and their revised structures

[0033] Figure 7 Preliminary anticancer activity evaluation of the synthesized advanced intermediates. (A) Cancer cell inhibition of the synthesized advanced intermediates at 20 µM concentration; (B) IC50 values of compounds 29 and 33.

Claims

1. A compound having anticancer activity, characterized in that, The compound is 1'- epi Intermediates 29 and 33 in the total synthesis of septosones B and C, said compounds exhibit significant anticancer activity against Hep G2, MV-4-11, and MOLT-4 cell lines. .

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