1
Introduction

1.1 Preview

From its early isolation by Baeyer from the reaction of indigo with a mixture of sulfuric acid and sulfuric anhydride [1], indole-indigo?+?oleum-has a remarkable history and has made a huge impact on society, as we will see in this chapter. The reader is referred to several general reviews on the chemistry and synthesis of indoles [2-11] and their role in society [12]. Reviews devoted solely to indole ring synthesis are tabulated in Section 7 in this chapter.

1.2 Indole-Containing Natural Products

Indole (1) itself has several interesting natural sources, the most familiar of which is mammalian feces [13, 14], although its toxicity is low (LD50?=?1,100?kg/mg in rats) [15]. Indole has also been identified in significant amounts in flowers (jasmine, narcissus, lilac, Easter lily, lemon flower, tuberose, and honeysuckle) and in trace amounts in other flowers and foods (clove, orchid, gardenia, coffee flower, Daphne odora, tomato, molasses, sesame seed, rye bread, cheese, aged casein, and aging fish) [15]. Despite its objectionable and pervasive odor at high concentration, at low levels indole as been used by perfumers to augment fragrances. The odor threshold of indole is 140 parts per billion, significantly higher than, for example, methyl mercaptan (0.02?ppb) and dimethyl sulfide (0.30-1.00?ppb) [15]. Indole is also a component of human sweat [16] and breath [17]. Indeed, almost 30% of the volatile head space of sweat is due to indole [16]. Along with several other odorants, indole is attractive to mosquitos (Anopheles gambiae) [18].

Other well-known indoles that have various natural sources are skatole (3-methylindole) (2), serotonin (3), L'tryptophan (4), tryptamine (5), the plant growth hormones 3-indoleacetic acid (6) and 4-chloro-3-indoleacetic acid (7) [19], the mushroom hallucinogen psilocin (8), and the indole-derived ancient dyes indigo (9) [20] and Tyrian Purple (10) [19] (Scheme 1).

Scheme 1 Well-Known Common Natural Indoles

The vast marine environment, which covers 70% of Earth's surface, provides a wealth of naturally occurring indoles, and several reviews are available [21-24]. According to Hamann, 95% of the marine tropical biosphere accounts for 34 of the 36 phyla of life on Earth [24]. Some recently discovered marine indoles are depicted in Scheme 2. Several eusyntyelamides (e.g., D (11)) were isolated from the Arctic bryozoan Tegella cf. spitzbergensis [25], and the indole 12 was discovered in the marine fungus Aspergillus sydowii [26]. A New Zealand ascidian Didemnum sp. has furnished the ß-carboline alkaloid didemnidine B (13) [27], and the toxin, bunodosine 391 (14) is part of the venom of the sea anemone Bunodosoma cangicum [28]. The Arctic hydrozoan Thuiaria breitfussi has yielded the novel breitfussin B (15) [29]. Tribromoindole (16) was found in the red alga Laurencia similis collected from Hainan Island, China, along with two other tribromoindoles [30].

Scheme 2 Representative Newly Discovered Marine Indoles

Our terrestrial environment also contains a wealth of naturally produced indoles, and some recent examples are shown in Scheme 3 [31-38]. The novel thiazolyl-indole barakacin (17) was found in the ruminal bacterium Pseudomonas aeruginosa strain Z10 [31]. Spirobacillene A (18) was isolated from a culture of Lysinibacillus fusiformis KMC003 derived from coal mine acidic drainage [32]. The Chinese plant Alocasia macrorrhiza has yielded the five new indole alkaloids alocasins A-E (19-23) [33]. Isocyalexin A (24) is the first plant-derived isocyanide to be discovered, isolated from rutabaga roots (Braesica napobrassica) [34]. The human pathogenic fungus Exophiala dermatitidis generates exophialin (25), and 8-hydroxyexophialin (26) is found in cultures of the mutant strain Me1-1 of Exophiala dermatitidis [35]. A component of the dauer larval stage pheromone of the nematode Caenorhabditis elegans is indole 27 [36]. The novel tryptorheedei B (29) is found in the seeds of Entada rheedei, a large woody liana growing in tropical Africa and Southeast Asia [38]. The corresponding N-sulfonyl-L-tryptophan (tryptorheedei A) accompanies 29.

Scheme 3 Representative Recently Discovered Terrestrial Indoles

Carbazoles and the related indolocarbazoles represent a huge collection of natural products, and some recently discovered examples are shown in Scheme 4. A marine Streptomyces sp. SCSIO02999 has yielded four new carbazolo-sesquiterpenes, dixiamycins A (30), B (31), oxiamycin (32), and chloroxiamycin (33) [39]. The novel ß-carboline 34 is found in the mushroom Mycena metata [40], and the extraordinary fradcarbazole A (35) is one of three related indolocarbazoles produced by the marine Streptomyces fradiae [41]. A series of new carbazole alkaloids, clausenawallines G-K (e.g., 36), was isolated from twigs of Clausena wallichii, a folk medicine plant distributed throughout Southeast Asia [42].

Scheme 4 Representative Recently Discovered Carbazoles, Carbolines, and Indolocarbazoles

1.3 Biological Activity of Indoles

All indoles probably have some biological activity. Kumar and colleagues have briefly tabulated the range of activities that indoles possess [43]. More generally, Rosén and colleagues compare the chemical space that is occupied by natural products and bioactive compounds as a strategic starting point for drug discovery [44]. Section 3 presents biological activities of indoles, and Section 4 covers those bona fide indole-containing pharmaceuticals.

A growing worldwide problem is drug resistance to disease-inflicting bacteria, such as MRSA (methicillin-resistant Staphylococcus aureus) [45, 46]. Several indoles show promise in treating these bacterial infections, such as aryloxyindole 37 [47], 2-aryl-5-nitroindole 38 [48], cationic peptide 39 [49], and pacidamycin D (40) [50]. Biofilm infections cause 17 million new cases and up to 550,000 fatalities per year in the United States. Menthyl indole 41 is very active against biofilm formation induced by several strains of S. aureus [51] (Scheme 5).

Scheme 5 Representative Antibacterial Indoles

Marine biofouling is a major problem to the shipping industry, but not to sponges, many of which produce antifouling compounds that inhibit settlement and smothering by barnacle larvae (Balanus improvisus). Some of these indole compounds are shown in Scheme 6. The novel cyclopeptide bromobenzisoxalone barettin 42 was isolated from the marine sponge Geodia barretti [52], and the marine ascidian Stomoza murrayi contains several brominated indole-3-carbaldehydes such as tribromoindole 43, both of which prevent larval settlement or overgrowth by other marine species [53]. The physostigmine-like alkaloid urochordamine A (44) from the tunicate Ciona savignyi has potent larval settlement and metamorphosis-promoting activity at 2?µg/mL [54]. The Mediterranean gorgonian Paramuricea clavata contains several antifouling indoles, such as 2-bromo-N-methyltryptamine (45) [55].

Scheme 6 Representative Antifouling Indoles

Antifungal activity is seen with indole RWJ-61907 (46), which inhibits the growth of Saccharomyces cerevisiae and Candida albicans [56]. The N-methylcryptolepine salt 47 shows activity against Cryptococcus neoformans and C. albicans, two fungi associated with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), and Aspergillus flavus [57]. Antiparasitic activity is observed for several indole diamidines, such as 48, which is active against Trypanosoma brucei rhodesiense and Plasmodium falciparum [58]. The glycosyl-isoindigo derivative 49 is active in vitro against Trypanosoma brucei rhodesiense, Trypanosoma cruzi Tulahuen (Chagas disease), Plasmodium falciparum (malaria), and Leishmania donovani (leishmaniasis [59]) (Scheme 7).

Scheme 7 Representative Antifungal and Antiparasitic Indoles

The final stage of HIV disease is AIDS. At the end of 2011 some 34 million people were living with HIV worldwide, and 1.7 million AIDS-related deaths were reported in 2011 [60]. Although these figures are lower than they were ten years ago, HIV drugs are still in great demand. Several indole derivatives show promise in this area (Scheme 8). Notably, indolyl aryl sulfones (e.g., 50...