Antibiotics antitumor

Boger developed his pyridine synthesis out of a need to eonstruet a pentasubstituted pyridine in an approach to the formal total synthesis of antitumor antibiotic streptonigrin 44. The requisite triazine 48 was produeed by using this methodology in an iterative sense with two different aza-heteroeyeles. Reaetion of thioamidate 46 with tetrazine 47, in a eyeloaddition/eyeloreversion sequenee, afforded 1,2,4-triaziene 48. Exposure of enamine 49 to 48 resulted in the formation of 50. This compound was elaborated into a eompound that intereepted Kende s synthesis of 44. ... 

Further variations on this methodology were explored in chemistry directed to the synthesis of antitumor antibiotic CC-1065 61. Intramolecular cycloaddition with concomitant loss of nitrogen transformed 62 into 63. Further manipulation gave 64 which served as a building block in the assembly of 61. 

Chemical biology of epotilones A-E, 16-member macrolide antitumor antibiotics 98AG(E)2015. 

Design and synthesis of analogs of dynemycin, antitumor antibiotic with an-thraquinone, 10-member enediyne, tetrahydropyridine, and oxirane fragments 99EJ01. 

Studies on asymmetric total synthesis of antitumor antibiotic, fredericamycin A 98YGK963. 

Synthesis of the densely functionalized heterocyclic system of antitumor antibiotics azinomycins AandB, azirino [l,2-<2]pyrrolidine derivatives 98SL1031. 

Total synthesis of antitumor antibiotic ER900482, 3.9-epoxy-3//-azirino[2,3-c]-l-benzazocine. 97YGK946. 

Synthetic studies on heteroanthracyclines, heteroanalogs of anthracycline antitumor antibiotics 97H(46)705. 

The antitumor antibiotic mitomycin C functions by forming cross-links in DNA chains. 

The strained bicyclic core of the antitumor antibiotic ncocarzinostatin was constructed by this method23. 

The densely functionalized cyclopentenyl core 11 of the potent antitumor antibiotic viridenomycin (12) was most recently prepared by treatment of enone 9 with second-generation Ru catalyst C (Scheme 2) [22]. This reaction proved to be very slow, requiring 3.5 days to give only incomplete formation of cyclization product 10 in 69% yield (86%, based on recovered 9). 

Also, a novel RCM-based approach to the 6-aza[3.2.1]bicyclooct-3-ene 103, and hence a formal total synthesis of the antitumor antibiotic (-)-peduncular-ine (104) (Scheme 20), was recently disclosed by Martin s group [70]. Initial ex-... 

Scheme 20 RCM-based construction of key intermediate 103 in a formal total synthesis of the antitumor antibiotic peduncularine (104) [70]...

Roseophilin (273), a deeply red-colored pentacyclic compound isolated from the culture broth of Streptomyces griseoviridis, is a novel antitumor antibiotic. Compound 273 possesses a topologically unique pentacyclic skeleton, consisting of a 13-membered macrocycle incorporated in an ansa-bridged azafulvene, which in turn is linked to a conjugated heterocyclic ring system. The absolute stereochemistry of roseophilin, as depicted in Fig. 9, was unknown until the first total synthesis published by Tius and Harrington in 2001 [125]. All syn-... 

The desymmetrization principle was also exploited in the synthesis of (+)-FR900482, an antitumor antibiotic isolated from Streptomyces sandaensis [155]. A prochiral propanediol was enzymatically desymmetrized using PSL to give the corresponding (S)-monoester as illustrated in Figure 6.59. 

Although, as stated above, we wiU mostly focus on hydrolytic systems it is worth discussing oxidation catalysts briefly [8]. Probably the best known of these systems is exemphfied by the antitumor antibiotics belonging to the family of bleomycins (Fig. 6.1) [9]. These molecules may be included in the hst of peptide-based catalysts because of the presence of a small peptide which is involved both in the coordination to the metal ion (essential co-factor for the catalyst) and as a tether for a bisthiazole moiety that ensures interaction with DNA. It has recently been reported that bleomycins will also cleave RNA [10]. With these antibiotics DNA cleavage is known to be selective, preferentially occurring at 5 -GpC-3 and 5 -GpT-3 sequences, and results from metal-dependent oxidation [11]. Thus it is not a cleavage that occurs at the level of a P-O bond as expected for a non-hydrolytic mechanism. 

H. Umezawa hoped to obtain immunostimulants from microbes, because, in cancer patients, the immune response is lowered. In 1972, H. Umezawa, T. Takeuchi, and M. Ishizuka (now Vice-Director of the Institute for Chemotherapy, a branch of IMC) found that the administration in mice of a small dose of diketocoriolin B, an oxidation derivative of the antitumor antibiotic coriolin B (1971), increases the number of mouse-spleen cells... 

Clinical study of a new antitumor antibiotic, bleomycin, T. Ichikawa, K. Matsumoto, and H. Umezawa, Int. Congr. Chemother. 5th, Vienna, (1967) 507-516. 

A new antitumor antibiotic, spergualin isolation and antitumor activity, T. Takeuchi, H. linuma, S. Kunimoto, T. Masuda, M. Ishizuka, M. Takeuchi, M. Hamada, H. Naganawa, S. Kondo, and H. Umezawa, J. Antibiot., 34(1981) 1619-1621. 

Rosazza JP (1978) Antitumor antibiotic bioactivation, biotransformation and deriva-tization by microbial systems. Recent Results Cancer Res 63 58-68... 

W. A. Renters, B. S. Iyengar, Cancer chemotherapeutic agents, va. Antitumor Antibiotics... 

Scheme 10.14 gives some other examples of Wolff rearrangement reactions. Entries 1 and 2 are reactions carried out under the classical silver ion catalysis conditions. Entry 3 is an example of a thermolysis. Entries 4 to 7 are ring contractions done under photolytic conditions. Entry 8, done using a silver catalyst, was a step in the synthesis of macbecin, an antitumor antibiotic. Entry 9, a step in the synthesis of a drug candidate, illustrates direct formation of an amide by trapping the ketene intermediate with an amine. 

Earlier model studies designed to explore the action of anthracycline antitumor antibiotics first noted a lability of QM adducts. QM1 was generated by oxidation of its precursor (QMP1) with silver oxide and shown to undergo reversible reaction... 

Angle, S. R. Rainer, J. D. Woytowicz, C. Synthesis and chemistry of quinone methide models for the anthracycline antitumor antibiotic. J. Org. Chem. 1997, 62, 5884-5892. 

Daunorubicin is an anthracycline that is sometimes referred to as an antitumor antibiotic. Daunorubicin inserts between base pairs of DNA to cause structural changes in DNA however, the primary mechanism of cytotoxicity is the inhibition of topoisomerase II. The pharmacokinetics are best described by a two-compartment model, with a terminal half-life of about 20 hours. The predominant route of elimination of daunorubicin and hydroxylated metabolites is hepatobiliary... 

Bleomycin Antitumor antibiotic Renal clearance Pulmonary fibrosis... 

The last step of the total synthesis of natural (+)-duocarmycin SA, a potent antitumor antibiotic, was accomplished by forming the amide bond with CDI in 74% yield [60]... 

---