Review Chemistry and Biology of Natural and Designed Enediynes K

Proc. Natl. Acad. Sci. USA Vol. 90, pp. 5881-5888, July 1993 Review Chemistry and biology of natural and designed enediynes K. C. Nicolaou*, A. L. Smitht, and E. W. Yue Department of Chemistry, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, CA 92037; and Department of Chemistry, University of California at San Diego, La Jolla, CA 92093 ABSTRACT Ever since the initial reports of the enediyne anticancer antibiotics in the late 1980s, researchers from a number of disciplines have been devoting increasing attention to their chemistry, biology, and potential medical applica- tions. Synthetic chemists and molecular designers have been engaged in attempts to synthesize these molecules and to model their unique architecture. Considerable efforts have been directed at understand- ing and mimicking the various processes involved in the targeting, activation, and DNA cleavage associated with these natural products. This review summarizes the main contributions to the field, with par- ticular emphasis on work from our laboratories. Highlights include studies of the Bergman reaction, which is central to the mechanism of action of enediynes, the design and chemical synthesis ofa number of these systems, and biological studies with selected molecules. Finally, the total synthesis of calicheamicin yI, the most 8: kedarcidin chromophore 9: neocarzinostatin chromophore prominent member of this class of naturally occurring compounds, is discussed. FIG. 1. Naturally occurring enediyne anticancer antibiotics. omatization when heated to give the ben- nostatin chromophore (9, Fig. 1) (12-14) Nature continually serves to provide sci- zene ring 4 with the intermediacy of the has also been grouped with the enediyne entists with new ideas, often provoking highly reactive 1,4-benzenoid diradical antibiotics due to the similarity of its us to reexamine previous studies and structure and mode of action. leading us in new directions. An example species 2. Masamune and coworkers (3) of an instance which has and Wong and Sondheimer (4) also ob- such captured served the cycloaromatization of 10- Molecular Structures, Biological the imagination of many scientists, our- and Mechanisms of Action of selves included, came in 1987 with the membered ring enediynes. However, the Properties, unveiling of a new class of natural prod- full significance of these simple observa- Naturally Occurring Enediynes ucts, the so-called "enediyne anticancer tions became apparent only when the antibiotics" (Fig. 1), which possess po- structures of calicheamicin -y (5, Fig. 1) Calicheamicin y1 (5), the most prominent tent anticancer activity and a hitherto and esperamicin A1 (6, Fig. 1), the first member of the calicheamicins, was iso- unseen biological mode of action (for a representatives of the enediyne antibiot- lated from Micromonospora echinospora previous review, see ref. 1). The story ics, were reported (5-8). For at the very ssp. calichensis and is a remarkable piece began some 15 years earlier, however, heart of these molecules is contained the of engineering by Nature, which has per- for it was in the laboratories of Robert same enediyne unit; and therein lies the fectly constructed the molecule to endow Bergman that the intriguing chemical means by which these unprecedented it with its extraordinary chemical and processes which provide the key to un- molecules exert their remarkable biolog- biological properties (15). These include derstanding the remarkable activity of ical properties. Dynemicin A (7, Fig. 1) activity in the biochemical prophage in- these antibiotics were first studied (2). (9, 10) and kedarcidin chromophore (8, duction assay at concentrations < 1 pM, The findings of Bergman are summarized Fig. 1) (11), representing structurally dis- high antibacterial activity, and extreme in Scheme I, in which the enediyne sys- tinct classes of enediyne antibiotics, potency against murine tumors such as tem 1 was observed to undergo cycloar- were subsequently reported. Neocarzi- P388 and L1210 leukemias and solid neo- plasms such as colon 26 and B16 melanoma with optimal doses of 0.15-5 ug/ DH kg. Calicheamicin -yl (5), along with the *To whom reprint requests should be ad- 2 4 dressed. tPresent address: Merck Sharp & Dohme Re- SCHEME I. Bergman's original design and observation regarding the thermal cycloaroma- search Laboratories, Terlings Park, Harlow, tization of enediynes. Essex CM20 2QR, U.K. 5881 Downloaded by guest on September 24, 2021 5882 Review: Nicolaou et al. Proc. Natl. Acad. Sci. USA 90 (1993) trigonal bridgehead position to a tetrag- onal center, causes a significant change in structural geometry which imposes a great deal of strain on the 10-membered ring. This strain is completely relieved by the enediyne undergoing the Bergman reaction, generating a highly reactive benzenoid diradical (12). The calicheamicin diradical abstracts hydrogen atoms from duplex DNA at the C-5' position of the cytidine in 5'-TCCT-3' and the C-4' position ofthe nucleotide three base pairs removed on the 3' side of the comple- mentary strand (21, 22), leading to cleavage of both strands of DNA. The mechanism of action ofthe structurally similar esperamicins is thought to be essentially the same as that of the calicheamicins. Dynemicin A (7), the first member of FIG. 2. Computer-generated model of DNA-bound calicheamicin -yI (5) along a TCCT site. the dynemicin subclass of enediyne anti- [Reprinted with permission from ref. 1 (copyright VCH, Weinheim, FRG).] biotics to be reported (9, 10), was discov- other enediyne antibiotics, is believed to iodo substituent of the hexasubstituted ered in the fermentation broth of Mi- exert its biological activity by aromatic ring and the cromonospora chersina. It exhibits very damaging exocyclic amino potent activity against a variety ofcancer DNA. Indeed, it is a highly potent DNA- substituents of the two guanines in the cell lines and significantly prolongs the cleaving agent giving rise primarily to 3'-AGGA-5' tract. Experimental evidence lifespan of mice inoculated with P388 sequence-selective double-strand cuts from our own laboratories supports the leukemia and B16 melanoma cells. Fur- (16). idea of an important role for the iodine in thermore, it exhibits promising in vivo The calicheamicin yA molecule contains the binding affinity ofthis oligosaccharide antibacterial activity with low toxicity. two distinct structural regions. The larger to DNA (20). Like the calicheamicins and esperami- of the two consists of an extended sugar The second region of calicheamicin yi cins, the dynemicins include in their mo- residue comprising four monosaccharide is its aglycon, a rigid, highly functional- lecular structures a 10-membered ring units and., one hexasubstituted benzene ized bicyclic core termed calicheamici- with a 1,5-diyne-3-ene bridge. They are, ring which are joined together through a none, which acts as the "warhead" ofthe however, unique in combining the highly unusual series of glycosidic, molecule. The enediyne functionality of enediyne unit with the anthraquinone thioester, and hydroxylamine linkages. It the molecule is locked within a rigid chromophore of the anthracycline anti- is this aryloligosaccharide which serves to 10-membered bridged ring awaiting acti- cancer antibiotics. deliver the molecule to its target, binding vation to undergo the Bergman reaction. A mechanism for the antitumor activ- tightly in the minor groove of double- Also forming part of the aglycon is a ity of dynemicin A (7) has been proposed helical DNA and displaying high specific- trisulfide, which serves as the trigger. which combines elements of the mecha- ity for sequences such as 5'-TCCT-3' and Once the molecule is in the vicinity of nisms of action of the calicheamicin/ 5'-TTTT-3' (16, 17) through significant DNA (whether prior or subsequent to esperamicin, neocarzinostatin, and an- hydrophobic interactions and other forces binding is not known), a series of chem- thracycline classes of antibiotics and (Fig. 2). This binding is thought to be ical events unfold which ultimately leads which is supported by the observation facilitated by substantial preorganization to DNA cleavage (Scheme II) (5-8). A that DNA strand cleavage by dynemicin of the oligosaccharide into a rigid, ex- nucleophile (e.g., glutathione) attacks the A is enhanced by the presence of thiols. tended conformation (18). Molecular central sulfur atom of the trisulfide In this mechanism (Scheme Im) (10), the modeling calculations by Schreiber and group, causing the formation of a thiolate anthraquinone nucleus intercalates into coworkers (19) suggested that a signiflcant or a thiol (10) which adds intramolecu- the DNA and undergoes bioreduction portion of the sequence selectivity for larly to the adjacent a,,4unsaturated ke- (not necessarily in that order), facilitating 5'-TCCT-3' arises from a favorable inter- tone embedded within the framework of opening of the epoxide. This causes a action between the large and polarizable the aglycon. This reaction, converting a significant conformational change in the molecule and introduces considerable strain into the enediyne system which is relieved by the new system undergoing the Bergman reaction, thus generating the DNA-damaging diradical species 17 (10). Molecular Design, Chemical Synthesis, and Biological Actions of Enediynes The reports of the structures of the calicheamicins and esperamicins, and their fascinating mode of action, prompted several groups to undertake investigation

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