Triterpenoid Quinonemethides and Related Compounds (Celastroloids) A. A. LESLIE GUNATILAKA, Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA Contents 1. Introduction ........................................ 2 2. General Structural Features and Nomenclature ................... 4 3. The Families of Celastroloids . .. 6 3.1. Quinonemethide Triterpenoids . .. 6 3.2. 14(15)-Enequinonemethide Triterpenoids . .. 7 3.3. 9(1l)-Enequinonemethide Triterpenoids ..................... 11 3.4. Phenolic and 6-0xophenolic Triterpenoids ................... 14 3.5. 7-0xoquinonemethide Triterpenoids ....................... 14 3.6. Dimeric Celastroloids . .. 15 3.7. Miscellaneous Celastroloids ............................ 18 4. Natural Occurrence . .. 18 4.1. Taxonomic Considerations . .. 18 4.2. Plant Sources of Celastroloids . .. 19 4.3. Distribution of Natural Ce1astroloids . .. 24 4.4. Celastroloids from Tissue Cultures ........................ 24 5. Derivatives of Celastroloids ............................... 27 6. The Chemistry of Celastroloids . .. 35 6.1. Isolation Techniques. .. 35 6.2. Structure Elucidation . .. 37 6.2.1. Early Structural Studies of Celastrol and Pristimerin . .. 37 6.2.2. Application of Spectroscopic Techniques . .. 42 6.2.2.1. UVjVIS and ORDjCD Spectroscopy .............. 42 6.2.2.2. Infrared Spectroscopy. .. 47 6.2.2.3. NMR Spectroscopy . .. 48 6.2.2.3.1. IH-NMR Spectroscopy. .. 49 6.2.2.3.2. 13C_NMR Spectroscopy ................ 59 A. A. L. Gunatilaka et al., Fortschritte der Chemie organischer Naturstoffe / Progress in the Chemistry of Organic Natural Products © Springer-Verlag/Wien 1996 2 A. A. L. GUNATILAKA 6.2.2.4. Mass Spectrometry . .. 70 6.2.2.5. X-Ray Crystallography . .. 74 6.3. Chemical Reactions ................................. 76 6.3.1. General Chemical Characterization .................... 76 6.3.2. Degradation and Oxidation . .. 76 6.3.3. Reduction and Derivatization . .. 79 6.3.4. Addition Reactions . .. 82 6.3.5. Rearrangements . .. 83 6.3.6. Photochemistry . .. 88 7. Partial Synthesis . .. 89 8. Biosynthetic Aspects ................................... 91 9. Biological Activity . .. 95 9.1. Antimicrobial Activity. .. 96 9.2. Antitumor Activity. .. 99 9.3. Other Biological Activities ............................. 103 10. Conclusions. 103 Addendum ............................................ 105 Acknowledgements ....................................... 114 References . 114 1. Introduction The triterpenoid quinonemethides constitute a relatively small group of unsaturated and oxygenated D:Alriedo-nor-oleananes. In nature these nor-triterpenoid pigments are found restricted to the higher plant family, Celastraceae (including Hippocrateaceae; see Sect. 4.1). For this reason, BRUNING and WAGNER (10) coined the general name "celastroloids" for this class of compounds, and in this review, this term is used exclusively for all natural triterpenoid quinonemethides and their structural rela­ tives. Celastroloids usually co-occur with other triterpenoid types like the D:Alriedo-oleananes and lupanes. Despite their structural complex­ ity and interesting biological activities, no comprehensive review devoted specifically to celastroloids has appeared to date. However, mention has been made of celastroloids in general reviews and handbooks dealing with other triterpenoid types (1, 26, 108, 123), terpenoids and steroids of Sri Lankan plants (80), constituents and phytochemistry of Celastraceae (10, 63, 70, 109), triterpene phenoldienones (110), phenolic triterpenoids of Sri Lankan Celastraceae (42, 84), and natural quinonemethides (16, 143, 144). Since approximately 70 celastroloids are presently known, a review devoted entirely to these is now appropriate. References, pp. 114-123 Triterpenoid Quinonemethides and Related Compounds 3 This review covers the literature included in Chemical Abstracts up to June 1994 and contains comprehensive discussions on distribution, structure elucidation, chemistry, biological activity and biosynthetic as­ pects of celastroloids. It also includes all their derivatives and related structures of semisynthetic origin and some unpublished data from our laboratory and those of others. Some conclusions on current status and future prospects are drawn at the end. The discovery of celastroloids and the history of their structure elucidation demand comment. The discovery of the most common triter­ penoid quinonemethides, celastrol (1) and pristimerin (11), and the stud­ ies which led to the establishment of their interrelationship will be considered here whereas the history of their structure elucidation will be discussed in Sect. 6.2.1. The powdered roots of Tripterygium wilfordii Hook. f. (family Celas­ traceae), called "lei king teng" ("thunder god wine") in Chinese, have been used in China for centuries as an insecticide. In 1930 the "thunder god wine" suddenly came into prominence in Chekiang province, China, as the result of a dispute regarding the damage to valuable and highly productive valley lands caused by rain water from the nearby hills following the harvest of Tripterygium roots, which left the soil loose, hence flooding the valley. The land owners of the valley had requested that the cultivation of T. wilfordii be forbidden. This quickly provoked a strong opposition from vegetable growers who complained that they could not grow their crops without using the powdered roots of T. wilfordii to kill noxious insects. Entomologists and other experts were sent to investigate the validity of this claim. As a result of these investiga­ tions, CHOU and MEl published the first paper on the root constituents of Tripterygium wilfordii in 1936 (15). They were able to isolate the insecti­ cidal principle (suspected to be an alkaloid) and dulcitol along with an insecticidally inert pigment named tripterine. Tripterine was later shown to be identical with celastrol obtained by GISVOLD from another Celas­ traceae species, Celastrus scandens (47). The first scientific paper dealing with celastrol was published in 1939 by GISVOLD who wrote, "One time some investigators thought that the chief pigment found in the outer bark of the root of Celastrus scandens was ~-carotene. ~-Carotene is of great importance because of its use as a standard for vitamin A, and therefore confirmation of its existence in a plant from which it might be easily isolated and purified was deemed advisable." However, to his disappointment, the pigment turned out to be different from ~-carotene. In GISVOLD'S words, "the bark of the root of Celastrus scandens contains no ~-carotene. A red pigment has been isolated and named celastrol" (47). GISVOLD was perhaps unaware that 4 A. A. L. GUNATILAKA BHARGAVA had given the same name to a phytosterol isolated from Celastrus paniculatus (5). Tripterygium wilfordii was introduced into the United States from China in 1941 after its claimed insecticidal activity had been demon­ strated (86). In 1942 SCHECHTER and HALLER (132) reisolated from T. wilfordii tripterine previously reported by Chinese workers and showed that it was identical with celastrol isolated by GISVOLD. In the early 1950's BHATNAGAR and DIVEKAR (6) were prompted to initiate chemical studies on an Indian Celastraceae species, Pristimeria indica, as there was a common belief among the people of North Kanara in India that a teaspoonful of the paste (obtained by rubbing the root of this plant on a stone with a little lime juice) administered orally twice a day for 3 days completely cured respiratory diseases. They were successful in isolating the antibacterial principle from the root bark of P. indica which sepa­ rated as bright orange needles and was named pristimerin. The probable relationship between pristimerin and celastrol was noted by KULKARNI and SHAH (102) and later by KAMAT, FERNANDES and BHATNAGAR (98). However, it was NAKANISHI'S group which firmly established that pris­ timerin is the methylated derivative of celastrol (118). Since the discovery of celastrol (tripterine) and pristimerin and the establishment of their structural interrelationship, a variety of celas­ troloids have been encountered in plants of the family Celastraceae (including Hippocrateaceae) and these are listed in Tables 1 through 8. 2. General Structural Features and Nomenclature In general, celastroloids incorporate the 24-nor-D : A- friedo-oleanane nucleus (Fig. 1) and invariably contain oxygenated functionalities at C-2 2 3 23 Fig. 1. Basic nucleus of celastroloids References, pp. 114-123 Olmeric Celastrolold. 1. oxldlltlon 8t C4I ~ 2. ring A a_tlzIItIon ;:; R, 0 ~ 6-Oxophenollc :;) -;-/HO 7-<>XoqulllOMlNthldes o 0: D c 5' o 1. methyl ahIft (11-- 8) :;) 2. Iou of H+ (e-i1) 3'" .. o ;.'" HO 0: '" III'" HO HO :;) e 1. oxidation at e-15 0- 1. oxidation 8t e-11 ~ QulnoMlMlhIdM 2. methyl ahl1l (14 ..... 5) :>:l 2. methyl ahl1l (e--11) 3.10 .. of H+ (e-1S) 3. 10.. of H+ (e-11) '";:;;- ;:; 0- n o 3 '1:lo c :;) 0- o '" Mltcelle_. Celaltrololds 14(15)-EnequinoMllMlthldes e(11~lnoMIMthldM V> Fig. 2. Major classes of celastroloids and their structural (biogenetic) interrelationship 6 A. A. L. GUNATILAKA and C-3, the only exception being celastranhydride (46) in which ring A has undergone oxidative cleavage. Other known sites of oxidation of the quinonemethide system are C-6 and C-7. Oxidation at C-6 affords the class of 6-oxophenolic nor-triterpenoids whereas oxidation at C-7 results in 7-oxoquinonemethides. Triterpenoid quinonemethides with addi­ tional unsaturation at C-9(11) or C-14(lS)