Medicinal Chemistry 562P 1. (34) Final Exam - Part A IL. (16) December 10, 2008 TIL (33) IV. (17) Please write neatly. TOTAL. (100) n Bendamustine (Treanda) is a new drug for the treatrnent of chronic lymphocytic leukemia (CLL). Hy i N ° 1 CH, —CHy—CHp—E—O-H CCH Ce 4 N SOue ci—cH, cH 1. Bendamustine is administered IV as its monohydrochloride salt, a (4 pts) Show the structure of this salt either on or next to the structure above, and estimateits pKa. poe > 7] b. pts) Explain why Bendamustine is given in its salt form, The drag is aclminisrerel IV, em mest le complerely olissolvedl iy solution. 2. (6 pts) Based on the structure of Bendamustine, describe its chemical class, where it acts in the cell cycle, a major toxicity, and its mechanism of action. Chemical class: Nitruain masturcl alle paring qo Cel cyge. coms Textethys BMD Mot: xXctiales DUA via Formection oP qu criviciaiuen ton , 3. (9 pts) Show mechanistically (arrow convention) how Bendamustine cross-links DNA, using the partial structure below. (NOTE: Show structure of intermediates.) oh hy Noty—cHy—cl 2 hi A iy ROB. pd Mec (cross-inked DNA) ete RNS hyrchy-ch | } {aziridinium ion) 7 a f Nuz CH > Obs wy RENE anys De Sey MS (monoalkyiated DNA)Presently, Fludarabine is the most widely used drug for the treatment of CLL. NH, . i N a. (4 pts) Circle all of the chiral carbon nZ \ atoms in the structure of Fludarabine. A, Nl a b. (3 pts) What is the absolute ° configuration around the starred (*) Ho=B-o: ©. . carbon atom? on HOH Ww Ho c. (4 pts) Fludarabine is an antimetabolite purine analogue. Might it be worthwhile to use Fludarabine in combination with Bendamustine? Why, or why not? Tt won lea noviyushile because H+ acty solediely & er the S-phase te olecweare pwd sqethesty alert) Bewdtrastine Aoouades otrreacls Dorwecl pasa. Seer IL. © Dasatinib (Sprycel. S a riew agent to treat CML. (aed L yb died Cry PCAC MW S POKembgen - OL excep les oul 1 (3 pts) Describe its mechanism of action. Dascctanio ranilorts Bey-Abole tyrorar Wneege whide wormed(cy presphery tare, ewckew preteias Prec —> c€ grolirtreetton CAL tf clarel cells thor Comkuit Tre clouovmer| Phttate| phos (4 pts) On or next to the structure above, draw one possible P450 oxidative metabolite of Seek Dasatinib and one Phase II metabolite of Dasatinib itself. Set chor (5 pts) Circle the amide structure in Dasatinib, and below, show a mechanism for general base- catalyzed hydrolysis of an amide. 5 (4 pts) Fungal infections often occur in patients on chemotherapy, and are treated with azole antifungal agents, Why might this be a problem with patients who are stablized on Dasatinib? scctanrb is metalvelirert by cubechwome PHXOs te 5 4S Yn acdive woke bo thes. TL thee Psy artis peo Wa azole aus Panga | aout s sy Wi PB conceuitrerbr ong Dasatiailo anc conich leak to V TOA, ( & AWutetheui nyML Ovarian cancer and pancreatic cancer are called “silent killers” because signs and symptoms usually do not occur until the cancers are already invasive. Ovarian cancer is treated aggressively with radiation, chemotherapy and surgery. The most common chemotherapy (CHAP) includes the nitrogen mustard alkylating agent, Cyclophosphamide (Cytoxan), the alkylating agent Hexamethylmelamine (Altretamine), the anthracycline antibiotic Adriamy cin (Doxorubicin), and the metalating agent Platinol (Cisplatin). 1. @pts) Describe where in the cell cycle each agent acts. Cycle ples amie ~ (one octal bontloming CONE Adlviam yada — ccn6 Platiuel — cons (6 pts) Give one major toxicity for Cyclophosphamide and Hexamethylmelamine, and two major toxicities for Adriamycin and Platinol, Sake Mes Maud ~ amd Wherecm tk ite ~ Bd t Aclviamyct — SMD) Carcltetericity Plakacl — Kidney Damage, Aeoutre Sere Domeql, ny, Ei ce (12) Desert the mechanism of on of ea of te furans ne ce Ags, drug truck is metatralirel $0 a Coda heigorrselt - (oe dhacndeapols wrartetnk Huck Lota en Oe aerate fete Toms, exawretnurtlamare — Atrutedion ed DUA Wret jm ate er re subtest shy ackiuiby te tae ome ze enact DAS, DAL ieedl aah Sete qke Ba eclicwed to packs sea 4 Da cereal Pladinol — rokdehtd Dud bit Xl ial Sep rsecide plilec Sasson 4s) Based on cal ec IE ee td nc Shantsis o action, would you consider this a good regimen? Why, or why Casecl on collecle casera Cot ae Hrreug eur pre ceM cyte) an different OR sy Hats Ty cutobee cae é ewe 5S. (4 pts) Based on toxicity spectrum, what biological response modifier would most likely be used, and why? DL ccute Ths ts a Very texte yeqginen CB gr lf couein Bmp) . Theretert one RR Vere wet eck ) see Sieh wr Pecreve Cues elu C-ESE eres Cecio 4 oe oc predlusckoen, (epee eco uty 6. (3 pts) Amifostine (Ethyol) is a newer chemoprotectant drug that is used to decrease toxicities associated with Platinol (Cisplatin). Describe how this agent works, Pre’ wt is hy hey rerk + Fe a thie aaeuct tnoty venaes ded 5 Cowles th ylabinwer) mM oy plein Kr) 3TV, _ Hexamethylmelamine (Altretamine) is sometimes used in treating ovarian cancers. 1. G pts) Show a reaction for oxidative N-demethylation of Hexamethylmelamine. a) x (CHy)2N, C Yo JO ¥oL a a M Pas, Sy b+ vow feo, Seer {4 ay Go t 4 © 2. Hexameethylmelamine (A) may also be con verted to a reactive metabolite that could damage DNA as shown in the partial scheme below. Hs eho“ (HN SA ye Ao en (Os No Brey | paso EY 3 N. N To” nw a (2 pts) Draw the structure of carbinolamine B. b. (1 pt) Product Cis formed enzymatically by Suto Woust@reys that utilize the cofactor PAPS. ©. (5 pts) Show (arrow convention) how C eliminates E to form D, and show the structure of E d (4 pts) Show (arrow convention) how D can alkylate DNA, and show the structure of F.