Key to Xenobiotic Carotenoids

A listing of carotenoids with heteroatoms (X = F, Cl, Br, I, Si, N, S, Se, Fe) directly attached to the carotenoid carbon skeleton has been compiled. The 178 listed carotenoids with C,H,X atoms demonstrate that the classical division of carotenoids into hydrocarbon carotenoids (C,H) and xanthophylls (C,H,O) has become obsolete.


Introduction
The number of natural occurring carotenoids registered in the relevant books on the topic has increased continuously: 19 carotenoids in 1934, 67 in 1948, 273 in 1971, 563 in 1987, 750 in 2004 [1-5]. The importance of the Carotenoids Handbook is evident for all those working frequently or occasionally with carotenoids. However, the extensive compilation of natural occurring carotenoids has ignored the existence of the numerous xenobiotic carotenoids [6]. The impact of the Carotenoids Handbook is overwhelming insofar that carotenoids with atoms other than C,H,O are barely thinkable. Carotenoids are still classified in two groups: carotenes (polyenes containing C,H) and xanthophylls (polyenes with C,H,O), and the occurrence of carotenoids with other atoms was not contemplated by the existing nomenclature rules. In contrast, the Natural Product Reports dedicate a specific chapter to steroids with heteroelements, sulfur flavonoids and heteroatom-substituted carbohydrates have been reviewed. [7][8][9][10]. Admittedly, no hetero-carotenoids have been detected so far in Nature, but OPEN ACCESS nonetheless, it is not incongruous to expect carotenoids from sea organisms to incorporate Cl (compounds 5Cl-8Cl in the list) [11]; the interactions between selenium and carotenoids support speculations about the existence of combination products [12][13][14]. After all, heterocarotenoids may not keep forever their status as xenobiotic compounds, though by then, xenophobia towards xenobiotic carotenoids may be encountered. In a historical review on the "Development of Carotenoid Chemistry 1922-1991" the first Br-, N-and S-carotenoids (4Br-9Br, 2N, 12S) were ignored [15]. When the author's first manuscript on carotenoid thioketones (1S-3S) was rejected by the referees, the honorary co-author commented the rejection as the logical consequence of working with bizarre compounds. The syntheses of selenium carotenoids (1Se-7Se) were regarded by some of the author's colleagues as a completely useless, ill-famed and ill-smelling occupation. Strangely enough, the summarizing speaker at the end of a carotenoid conference intentionally omitted to mention the author's presentation on S, N and Se carotenoids. Fortunately, these narrow-minded discriminatory prejudices have now tended to cease; heterocarotenoids have found applications impossible to achieve with "normal" carotenoids, e.g., 2S, 15S, 3Se, 12N, 46N [16][17][18][19].
Despite the increasing interest in xenobiotic carotenoids, searching the databases for these compounds often results in zero hits. The unawareness of heterocarotenoids may perhaps be the reason for avoidable syntheses. The molecular wire carotenoid thiol 15S was prepared in several steps [16]. Carotenoid thione 2S, synthesized previously from a commercial carotenoid in a one-step synthesis, could probably have been more appropriate for the investigation [20]. Even an author sensitized to xenobiotic carotenoids witnessed ignorance; compounds 25N, 27N, 29N were not cited in a paper on carotenoid oxime hydrochlorides 19N-22N [21,22]. Unfamiliarity with heterocarotenoids is possibly the cause for further lack of mention, e.g., nitrile carotenoid 6N was patented in 1990 and published in 2011 without referring to previous work from 1988; thienyl carotenoid 3S, first reported in 1981, was not cited when the compound was resynthesized 20 years later (for an explanation of the designation 3S see Section 4: Nomenclature).
This thematic issue of Molecules on "Carotenoids" now offers the opportunity to compile a systematic listing of xenobiotic carotenoids. This inventory is a first attempt to take these carotenoids out of their obscurity.

Historical Remarks
Carotenoids became eye-catching in 1906 with the invention of chromatography by Tswett and got scientific consecration with the first determination of their molecular formula by Willstäter in 1907 [23,24]. During the period of structure determination the first nitrogen carotenoids were prepared as analytical derivatives (oxime, semicarbazone) [25,26]. Bromo and sulfur carotenoids were synthesized in 1958 and 1959 and chloro carotenoids in 1976 [27-29]. The synthesis of carotenoid amines was not successful until 1990 [30][31][32]. The most heterogenic carotenoids are probably iron carbonyl compounds 5Fe-7Fe. The common Greek-letter termed cyclic end groups are now increasingly being replaced by heterocycles.

Selection Criteria
Polyenes with a branched polyene chain >C20 capped with different cyclic or acyclic end groups and with heteroatoms covalently bound to the carbon carotenoid were considered. Thus, compounds with a heteroatom linked via oxygen to the carotenoid scaffold were omitted (e.g., phosphates). Adhering strictly to the isoprenoid nature of carotenoids would not allow including the interesting aza compound 37N [33]. This compound has been perceived as an azine of retinal, but is much more attractive when viewed as a diazapolyene. Various carotenoid derivatives prepared for analytical purposes (oximes, hydrazones amides etc.) are not mentioned [34,35], unless the derivative has also found an application extending characterization, e.g., canthaxanthin oxime was skipped, canthaxanthin oxime hydrochloride 21N as a surface active hydrophilic carotenoid was included [22]. Some carotenoids are drawn in the concise all-trans form, since the dimension of the actual cis-isomers would be too space demanding, e.g., 32N and 33N. The main concern of the recording, the heteroatom character of the compound, is not affected by this presentation.
In a departure from Molecules' normal style, reference registration in the compound list follows the example of the handbooks excluding article title and search-irrelevant data on the length of a paper. The references for the individual compounds are not exhaustive. A reader interested in a particular compound should perform a structural search in a database to receive complete and updated citations.
There certainly exist more xenobiotic carotenoids than presented in the list. Many hetero-carotenoids, especially from the patent literature, are not recorded owing to search problems or involuntary neglect. Such compounds ought to be included in a forthcoming extended register. Enlarging the selection criteria to <C20 chains, to xenobiotic C,H,O carotenoids, considering heteroatoms outside the carotenoid carbon skeleton sphere and taking into account ionic bounded heteroatoms is desirable for future compilation [36,37]. It would furthermore be valuable to have at hand a complete directory of isotope-substituted carotenoids (D, T, 13 C, 14 C) [38][39][40]. A catalog of modified carotenoids (e.g., long chain carotenoids, carotenoid dimers, carotenoids with deviated conjugation, hydrophilic carotenoids) and of compounds where carotenoids are part of other molecule classes (e.g., carotenoid lipids, antioxidant combinations) would likewise be desirable [41][42][43][44][45][46][47][48][49][50][51].

Nomenclature
The designation "xenobiotic carotenoids" is synonymously used with the term "heterocarotenoids". Whereas "heterocarotenoids" may appear more precise, the prefix hetero-is too strongly linked with heterocyclic chemistry and could create confusing expressions such as heterocyclic heterocarotenoids. Xenobiotic is, at present, the more explanatory designation.
Applying the nomenclature rules to xenobiotic carotenoids can lead to unintelligible descriptions; consequently, many authors have avoided naming their products, e.g., 11Cl-15Cl [52]. Keeping in mind that a short trivial name engenders more associative information than a (semi)systematic designation, some names in the list may appear randomly chosen or meaningless. A name search in a database will, therefore, often be unsuccessful, e.g., the name dicyano-C48:15 for 9N is certainly not canonical, but articulates the essential information: a dicyano substituted carotenoid of 48 C with 15 conjugated double bonds. The exact name would hide this evidence. In any case, the interested reader should certainly scrutinize the carotenoids visually and not by their appellation, and a structure search in a database is, therefore, recommended. The structures are approximately listed according to increasing structural complexity; however, the relation to a parent compound was considered more important than complexity ranking.
Aryl carotenoids have been recorded separately within a heteroatom section. Natural occurring aryl carotenoids display trimethylbenzene  or  end groups. Phenyl end groups without methyl are identified as either 16,17,18-trinor- or 16,17,18-trinor-; nevertheless, the letter  is preferred, in analogy to the widely used short form of forphenyl [53]. Thus, all carotenoids with a benzene ring are termed -carotenoids; the -ring positions are indicated as recommended by the nomenclature rule.
The compounds were arbitrarily numbered; the numbers are not intended to reflect the appointed personal identification digits used in the Key to Carotenoids and the Carotenoids Handbook [4,5]. Carotenoids with heterocycles were, for example, enumerated as xS, S indicating a cycle with sulfur.
The catalog of xenobiotic carotenoids definitely proves that the term xanthophyll has become obsolete [54]. Applying the classical two level differentiation − hydrocarbon carotenoids (C, H) and xanthophylls (C,H,O)-simply implies denying the existence of the listed 178 carotenoids. The use of xanthophyll is therefore discouraged and should be replaced by oxygen carotenoids; such a designation is unequivocally extendable to sulfur (nitrogen, halogen…) carotenoids.