Mitomycins syntheses: a recent update Jean-Christophe Andrez Review Open Access Address: Beilstein Journal of Organic Chemistry 2009, 5, No. 33. Department of Chemistry, University of British Columbia, 2036 Main doi:10.3762/bjoc.5.33 Mall, Vancouver, BC, V6T1Z1, Canada Received: 09 January 2009 Email: Accepted: 28 May 2009 Jean-Christophe Andrez - [email protected] Published: 08 July 2009 Editor-in-Chief: J. Clayden Keywords: antitumour; bioactivity; mitomycin; mitosene; synthesis © 2009 Andrez; licensee Beilstein-Institut. License and terms: see end of document. Abstract Mitomycins are a class of very potent antibacterial and anti-cancer compounds having a broad activity against a range of tumours. They have been used in clinics since the 1960’s, and the challenges represented by their total synthesis have challenged generations of chemists. Despite these chemical and medicinal features, these compounds, in racemic form, have succumbed to total synthesis only four times over the last 30 years. Review Introduction The mitomycins pose unique challenges to the synthetic their apparent fragility, mitomycins were rapidly identified to chemist. As S. Danishefsky noted, “The complexity of the act as prodrugs and their unique activity was thought to problem arises from the need to accommodate highly inter- originate from their ability to transform in vivo to generate the active functionality in a rather compact matrix and to orches- active metabolite. This was followed by decades of investiga- trate the chemical progression such as to expose and maintain tions to understand in detail their singular mode of action. It vulnerable structural elements as the synthesis unfolds. The was found that the aziridine played a crucial role, allowing an synthesis of a mitomycin is the chemical equivalent of walking irreversible bis-alkylation of DNA [3]. The decisive role of the on egg shells.” aziridine is far from unusual since its presence in a small number of other naturally occurring molecules such as azino- The first discovery of a mitomycin (mitomycin C, Scheme 2, mycins [4,5], FR-900482 [6], maduropeptin [7], and compound 7) dated from 1958 [1]. Its structural elucidation was azicemicins [8] is accompanied by significant biological proper- remarkable at that time considering the presence of 4ties (Scheme 1) [3,9]. Mitomycin C, 7, the most potent mito- contiguous stereogenic carbons in the molecule. The tetracyclic mycin, has been used medicinally since the 1970’s for its pyrrolo-indole skeleton of a mitomycin is embellished with an activity against breast, stomach, oesophagus and bladder aziridine ring, a carbamoyl moiety and a bridged carbinolamine tumours [9]. Besides the well-known antibiotic and antitumour packed in a constrained architecture [2]. The presence of such a properties of these compounds [9-12], other semi-synthetic concentration of functional groups renders this molecule only derivatives were prepared for investigation in clinical trials [13, moderately stable to bases, acid and nucleophiles but particu- 14]. larly reactive in presence of reducing agents. Notwithstanding Page 1 of 36 (page number not for citation purposes) Beilstein Journal of Organic Chemistry 2009, 5, No. 33. Scheme 1: Aziridine containing natural products. Altogether, the biological features of the mitomycins and the well as other soft and solid tumours [22]. The seven most challenges represented by their total synthesis have continually abundant mitomycins (A to K) in nature are presented in drawn the attention of numerous brilliant chemists who Scheme 2. conceived many different routes for their synthesis. However, only four total syntheses have been achieved [15-20]. Also, this Since many synthetic attempts did not succeed in providing review will summarize the current state of the art concerning mitomycins per se but only close relatives of these molecules, a the chemistry and biology of mitomycins. It will show and special nomenclature has been elaborated for these compounds: comment on the methodologies that have been successfully structures of type 15, which do not contain an aziridine ring, but employed in total syntheses as well as approaches leading to mitomycin analogs. The review will focus on the synthetic liter- ature of the past 30 years. From time to time earlier references will be provided to give background information. The mito- mycin’s close cousins, the FR family (Scheme 1, compounds 3 and 4) will not be discussed, nor will the different strategies that have been employed to improve the efficacy of mitomycins in vivo by structure activity relationship studies. As a matter of fact, the natural products themselves are so sensitive that only minor modifications have been possible in connection with medicinal chemistry studies. Discussion 1. Mitomycin isolation and nomenclature Mitomycins are natural products isolated from extracts of genus Streptomyces, a filamentous gram-positive soil bacterium that produces a wide array of biologically active compounds, including over two-thirds of the commercially important natural-product metabolites [21]. Mitomycin C is extracted from the bacterium Streptomyces lavendulae and is far from the most known compound of the series. It has become one of the most effective drugs against non-small-cell lung carcinoma, as Scheme 2: Mitomycin structures and nomenclature. Page 2 of 36 (page number not for citation purposes) Beilstein Journal of Organic Chemistry 2009, 5, No. 33. Scheme 3: Base catalysed epimerization of mitomycin B. bear the p-quinone are called mitosanes or mitosenes depending reversibly deprotonates the activated C9 position to give the whether they are at the oxidation state of an indoline (Y1 or Y2 more stable isomer 18 (Scheme 3) [27]. The basis of this = H) or an indole (Y1 = Y2 = C=C). Compounds bearing an surmise was the finding that mitomycin B eliminates carbamic aziridine at C1 and C2 are described specifically as aziridi- acid at the C10 position in basic medium whereas the angular nomitosanes and aziridinomitosenes respectively. Compounds methoxy series (mitomycin C), which can not open to the amino possessing a hydroquinone (protected or not) in place of the ketone, needs a better leaving group (such as a sulfonate). original quinone are identified by inclusion of the prefix leuco in reference to the Greek word leukos (clear, white) and the lack 2. Biology of intense color usually specific of the corresponding quinone 2.1. Biosynthesis ring. A significant amount of information on the biosynthesis of mitomycin C has been accumulated since 1970 [28]. The The mitomycins A and C differ only by the substituents on the mitosane core was shown to be derived from combination of quinone ring and transformation from 6 to 7 is realized by 3-amino-5-hydroxybenzoic acid 20 (AHBA), D-glucosamine 21 simple treatment with ammonia [23,24]. The mitomycins F, 8, and carbamoyl phosphate (Scheme 4) [29-32]. The key interme- and porfiromycin, 9, are synthesized by methylation of the diate, AHBA, is also a common precursor to other anticancer aziridine of mitomycin A and mitomycin C, respectively. Mito- drugs, such as rifamycin and ansamycin. mycin G, 12, mitomycin H, 13, and mitomycin K, 14, are deriv- atives of this first series obtained by elimination of the 2.2. Mode of action carbamate at position 10 [25,26]. Mitomycin B, 10, and mito- Mitomycins are quinone antitumor antibiotics that exert their mycin D, 11, possess the opposite absolute configuration of the biological activity through DNA alkylation and cross-linking. asymmetric carbon C9. Interestingly, Hornemann proved that The success of mitomycin C in cancer treatment is due to a this carbon could be easily epimerized to give 9-epi-mitomycin great cytotoxic selectivity for hypoxic (O2-deficient) cells char- B, 19. This compound showed better activity than the non- acteristic of solid tumors [33,34]. Mitomycin C itself is indeed epimerized one. He proposed a based-catalyzed mechanism relatively unreactive toward DNA [35,36] but becomes remark- wherein the tetracyclic-pyrolido-indole structure 10 opens up ably reactive upon reduction (enzymatic, electrochemical or reversibly at the bridged carbinolamine junction to give the chemical) by the mechanism shown in Scheme 5 [37-39]. This eight-membered ring 17. The base, in this case DBU, then mechanism was proposed 40 years ago based purely on struc- Scheme 4: Biosynthesis of mitomycin C (MMC) 7. Page 3 of 36 (page number not for citation purposes) Beilstein Journal of Organic Chemistry 2009, 5, No. 33. Scheme 5: Mode of action of mitomycin C. tural considerations and has been accepted since [40]. Only the 3. The N–C3–C9a disconnection first reductive activation step has been questioned as to whether it proceeds by a one-electron reduction to give the semiquinone [41-44] or by a two-electron reduction to give the hydroquinone [45-47]. Studies have shown that one-electron reduction in an organic solvent can trigger formation of the semiquinone and the subsequent reaction cascade [42]. On the other hand, two- electron reduction led to formation of the stable hydroquinone, which can be oxidized back to the quinone in the presence of Scheme 6: The N–C3–C9a disconnection. oxygen [48]. Nonetheless, different results were observed in water where both one- and two-electron reductions gave the same DNA adducts. Moreover, the disproportion of the 3.1. Danishefsky. Mitomycin K (MMK) semiquinone in aqueous anaerobic medium is also very fast [49] The retrosynthetic approach of Danishefsky is based on an whereas under aqueous aerobic conditions, the semiquinone intramolecular Diels–Alder reaction between a nitrosoaryl and a reoxidizes to the quinone more quickly than it disproportion- suitably functionalized diene (Scheme 7) [19]. Historically, this ates [50]. Thus, the conclusion was made that in aqueous strategy was designed to synthesize the related natural product medium the same hydroquinone intermediate was responsible FR-900482, 4, but their investigations also led to this signi- for the reaction cascade. ficant and concise total synthesis of mitomycin K.