Martyn Inman

Indole synthesis – something old, something new

Indoles, both naturally occurring and synthetic, exhibit wide-ranging biological activity. Unusual and complex molecular architectures occur among their natural derivatives. As a result, this important ring system continues to attract attention from the international chemical community, and new methodologies for the construction of this ever relevant heteroaromatic ring continue to be developed. Unfortunately, many methods frequently start from ortho-substituted anilines, thereby greatly restricting the availability of starting materials. A more general approach would start from a mono-functionalized arene such as an aniline or halobenzene, followed by cyclization with C–C or C–N bond formation to an unactivated C–H bond. Such methods are the subject of this perspective.

Two-Step Route to Indoles and Analogues from Haloarenes: A Variation on the Fischer Indole Synthesis

In a new variation on the Fischer indole synthesis, readily available haloarenes are converted into a wide range of indoles in just two steps by halogen-magnesium exchange and quenching with di-tert-butyl azodicarboxylate, followed by reaction with aldehydes or ketones under acidic conditions. The protocol, which is readily extended to the preparation of indole isosteres, 4- and 6-azaindoles and thienopyrroles, obviates the need to prepare potentially toxic aryl hydrazines, simultaneously avoiding undesirable anilines such as naphthylamines.

Synthesis of Indolequinones from Bromoquinones and Enamines Mediated by Cu(OAc)2·H2O

A Cu(II)-mediated synthesis of indolequinones from the corresponding bromoquinones and enamines is reported. The key oxidative cyclization proceeds in good yield for a broad range of substrates and can be performed on a multigram scale, allowing access to biologically interesting structures.

Synthesis of the Reported Pyranonaphthoquinone Structure of the Indoleamine-2,3-dioxygenase Inhibitor Annulin B by Regioselective Diels–Alder Reaction

Annulin B, isolated from the marine hydroid isolated from Garveia annulata, is a potent inhibitor of the tryptophan catabolizing enzyme indoleamine-2,3-dioxygenase (IDO). A synthesis of the reported pyranonaphthoquinone structure is described, in which the key step is a regioselective Diels-Alder reaction between a pyranobenzoquinone dienophile and a silyl ketene acetal diene.

Antitumour indolequinones: synthesis and activity against human pancreatic cancer cells

An important determinant of the growth inhibitory activity of indolequinones against pancreatic cancer cells is substitution on the 2-position with 2-unsubstituted derivatives being markedly more potent. A series of indolequinones bearing a range of substituents on nitrogen and at the indolylcarbinyl position was prepared by copper(II)-mediated reaction of bromoquinones and enamines, followed by functional group interconversions. The compounds were then assayed for their ability to inhibit the growth of pancreatic cancer cells. The pKa of the leaving group at the 3-position was shown to influence growth inhibitory activity that is consistent with the proposed mechanism of action of reduction, loss of leaving group and formation of a reactive iminium species. Substitutions on the indole nitrogen were well tolerated with little influence on growth inhibitory activity while substitutions at the 5- and 6-positions larger than methoxy led to decreased activity. The studies presented define the range of substitutions of 2-unsubstituted indolequinones required for optimal growth inhibitory activity.

Total Synthesis of the Cyclic Dodecapeptides Wewakazole and Wewakazole B

The cyclic dodecapeptides wewakazole and wewakazole B have been synthesized by a divergent strategy via a common tris-proline containing oxazole octapeptide and two separate bis-oxazole containing tetrapeptide units, followed by peptide coupling and macrocyclization. The three oxazole amino acid fragments are readily accessible by rhodium(II)-catalyzed amide N-H insertion of diazocarbonyl compounds, or by the cycloaddition of rhodium carbenoids with nitriles.

Origin of the Thiopyrone CTP-431 “Unexpectedly” Isolated from the Marine Sponge Cacospongia mycofijiensis

An intriguing hypothesis that latrunculin A, a well-known natural product, might have undergone transformation into the unprecedented thiopyrone CTP-431 upon long-term storage in methanol is advanced. Thus, opening of the hemiacetal of latrunculin A, followed by E1CB elimination, and dehydration would give a polyene that could undergo intramolecular Diels-Alder reaction, followed by methanolysis of the thiazolidinone ring and ring closure by intramolecular thiol addition to an enone. Experimental evidence that the novel thiazolidinone to thiopyrone rearrangement can occur is presented.

Abstract C176: Activity of novel indolequinone inhibitors of thioredoxin reductase 1 in pancreatic and colon cancers and in melanomas. Signaling mechanisms underlying antiproliferative activity.

Novel indolequinones (including QG001, 5-methoxy-1-methyl-3-[(2,4,6-trifluorophenoxy)methyl]-1H-indole-4,7-dione and NJ824, 2-(hydroxymethyl)-5-methoxy-1-methyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione) demonstrated marked anti-proliferative activity in MIAPaCa-2 and BxPC-3 pancreatic cancer cells as well as in colon, melanoma and renal cell lines as indicated by testing in the NCI-60 cell line screen. In studies using MIAPaCa-2 and BxPC-3 cell lines we examined the mechanism of action of lead IQs and results demonstrated inhibition of the selenoprotein thioredoxin reductase 1 (TR1) and induction of apoptosis in pancreatic cell lines at doses approximating their IC50 values obtained from MTT growth inhibition assays. Other selenoproteins such as glutathione peroxidase were not inhibited and the depletion of cellular thiols was not observed following treatment with lead IQs indicating target selectivity. The mechanisms underlying IQ-induced apoptosis were investigated and lead IQs were found to induce oxidation of cellular thioredoxin subsequent to inhibition of thioredoxin reductase 1 and downstream activation of p38 and JNK leading to apoptosis. IQ-induced apoptosis could be inhibited by the use of p38 and JNK inhibitors in MIAPaCa-2 cells confirming the importance of this pathway. The role of ASK1 as an intermediary MAPKKK modulating signaling from oxidation of thioredoxin to activation of p38 and JNK was investigated in MIAPaCa-2 cells overexpressing ASK1 and lead IQs were found to induce ASK1 phosphorylation. Studies were extended to panels of eighteen human colorectal cancers and nineteen pancreatic cancer cell lines and lead IQs were found to exhibit marked growth inhibitory activity with IC50 values ranging from 0.05 to 0.5 micromolar. In vivo studies were performed in xenograft systems and lead IQs demonstrated significant growth inhibitory activity in both pancreatic and melanoma xenografts. These data demonstrate that this class of IQ has marked growth inhibitory activity in pancreatic, colon and melanoma tumors and are worthy of further translational evaluation as potential therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C176.