Serendipity in anticancer drug discovery

Table 1 The sources used to identify serendipitous discoveries in drug development

Titles	Authors
Laughing Gas, Viagra, and Lipitor: The Human Stories Behind the Drugs We Use	Li[1]
Happy Accidents: Serendipity in Modern Medical Breakthroughs	Meyers[2]
Drug Discovery, a History	Sneader[3]
Chance favors the prepared mind-from serendipity to rational drug design	Kubinyi[4]

Table 2 List of drugs discovered by serendipitous events in the laboratory and their derivatives

Serendipitous drugs	Derivatives	No. of derivatives
Acetanilide	Acetaminophen	1
Acetohexamide	Tolbutamide, glimepiride, glibenclamide, glipizide, chlorpropamide, gliquidone, tolazamide, gliclazide	8
Captopril	Ramipril, fosinopril, lisinopril, trandolapril, enalapril, perindopril, spirapril, quinapril	8
Cisplatin	Oxaliplatin, carboplatin	2
Diethylstilbestrol	Dienestrol	1
Digoxin	Digitoxin, deslanoside, acetyldigitoxin, ouabain	4
Ergotamine	Dihydroergotamine, dihydroergotoxine, ergoloidmesylate, methysergide, methylergonovine, ergonovine	6
Ephedrine	Pseudoephedrine, ritodrine, metaraminol, phenylephrine, isoetharine, fenoterol, epinephrine, orciprenaline, terbutaline	9
Griseofulvin	NA	0
Heparin	Pentosan, polysulfate, enoxaparin, ardeparin, fondaparinux sodium	4
lsoniazid	NA	0
Lidocaine	Prilocaine, tocainide, mepivacaine, bupivacaine, levobupivacaine, ropivacaine	6
Lithium	NA	0
Marinol	Nabilone	1
Mechlorethamine	Chlorambucil, cyclophosphamide, melphalan, uracil mustard, estramustine	5
Mecillinam	Pivmecillinam	1
Methotrexate	Leucovorin	1
Nalidixic acid	Rosoxacin, enoxacin, pefloxacin, norfloxacin, lomefloxacin, ciprofloxacin, levofloxacin, ofloxacin	8
Nitroglycerine	Erythrityl tetranitrate, Isosorbide dinitrate	2
Penicillin	Ampicillin, amoxicillin, azidocillin, azlocillin, bacampicillin, carbenicillin, cloxacillin, cyclacillin, dicloxacillin, flucloxacillin, hetacillin, meticillin, mezlocillin, nafcillin, oxacillin, penicillin g, penicillin V, piperacillin, pivampicillin, tazobactam, ticarcillin	21
Pentamidine	NA	0
Physostigmine	NA	0
Quinine	Quinidine	1
Sorafenib	NA	0
Streptomycin	Framycetin, neomycin, josamycin, tobramycin, kanamycin, candicidin, spectinomycin	7
Sulfanilamide	Silver sulfadiazine, sulfacetamide, sulfacytine, sulfadiazine, sulfadimethoxine, sulfadoxine, sulfamerazine, sulfamethizole, sulfametopyrazine, sulfamethoxazole, sulfamoxole, sulfapyridine, sulfisoxazole	13
Valproic acid	Divalproex sodium	1
Vinblastine	Vincristine, vindesine, vinorelbine	3
Dicoumarol	NA	0
Warfarin	Acenocoumarol, phenprocoumon, dicumarol	3
Zinc Sulfate	NA	0

NA: Not available.

Table 3 List of drugs discovered to be beneficial for conditions other than for which they were developed (clinical)

Off-label drugs	Derivatives	No. of derivatives
Aminoglutethimide	NA	0
Alprostadil	Dinoprostone, carboprost, tromethamine, dinoprost, tromethamine, misoprostol	4
Amphetamine	Phentermine, methamphetamine, dextroamphetamine, alverine, selegiline, mephentermine, tranylcypromine, phenelzine, benzphetamine, diethylpropion	10
Aspirin	NA	0
Auranofin	NA	0
Carbamazepine	Oxcarbazepine	1
Celecoxib	NA	0
Chlordiazepoxide	Diazepam, temazepam, oxazepam, fludiazepam, clorazepate, halazepam, prazepam, flurazepam, lorazepam, cinolazepam, clonazepam, nitrazepam, bromazepam, flunitrazepam, quazepam, clotiazepam, alprazolam, estazolam, adinazolam, midazolam	20
Chlorothiazide	Benzthiazide, diazoxide, hydrochlorothiazide, hydroflumethiazide, bendroflumethiazide, cyclothiazide, polythiazide, trichlormethiazide, methyclothiazide, furosemide, bumetanide	11
Clofibrate	Fenofibrate	1
Dactinomycin	NA	0
Diisopropylfluorophosphate	NA	0
Diltiazem	NA	0
Dimenhydrinate	NA	0
Diphenhydramine	Bromodiphenhydramine, diphenylpyraline	2
Diphenoxylate	Loperamide	1
Dipyridamole	NA	0
Disulfiram	NA	0
Doxorubicin	Epirubicin, daunorubicin, idarubicin, valrubicin, plicamycin	5
Etomidate	NA	0
Finasteride	Dutasteride	1
Guanethidine	Debrisoquin, guanidine	2
Haloperidol	Droperidol	1
Imatinib	NA	0
Imipramine	Trimipramine, desipramine, clomipramine, protriptyline, amitriptyline, nortriptyline, cyclobenzaprine, maprotiline, doxepin, amoxapine	10
Iproniazid	Isocarboxazid	1
Linezolid	NA	0
Lysergic acid diethylamide	Cabergoline, lisuride, bromocriptine, nicergoline, pergolide	5
Meprobamate	Carisoprodol	1
Mercaptopurine	Thioguanine, azathioprine	2
Metronidazole	Tinidazole	1
Mifepristone	NA	0
Minoxidil	NA	0
Mycophenolic acid	Mycophenolatemofetil	1
Naloxone	Naltrexone	1
Norethindrone	Levonorgestrel, norgestrel, etonogestrel, gestodene,desogestrel, medroxyprogesterone, megestrol, progesterone, drospirenone, norelgestromin, ethynodioldiacetate	11
Pethidine	Anileridine	1
Phenobarbital	Methylphenobarbital, secobarbital, metharbital, aprobarbital, primidone, methsuximide	6
Prednisone	Medrysone, methylprednisolone, prednisolone, rimexolone, fluocortolone, desoximetasone	6
Probenecid	NA	0
Procarbazine	NA	0
Promethazine	Acepromazine, aceprometazine, acetophenazine, arphenazine, chlorpromazine, ethopropazine, fluphenazine, mesoridazine, methotrimeprazine, perphenazine, pipotiazine, prochlorperazine, promazine, propericiazine, propiomazine, thioproperazine, thioridazine, trifluoperazine, triflupromazine, trimeprazine	20
Quinacrine	Chloroquine, primaquine, hydroxychloroquine, amodiaquine	4
Reserpine	Deserpidine, rescinnamine	2
Salicyclic acid	Salsalate, olsalazine, diflunisal, mesalazine	4
Sildenafil	Tadalafil, vardenafil	2
Sirolimus	Everolimus	1
Tamoxifen	Toremifene	1
Terfenadine	Fexofenadine	1
Thalidomide	Lenalidomide	1
Tolazoline	NA	0
Trimethadione	Paramethadione	1
Zidovudine	Trifluridine, telbivudine, idoxuridine, zalcitabine, stavudine	5

NA: Not available.

Table 4 List of drugs discovered with the aid of serendipity in the laboratory, the number of identified derivatives and their therapeutic notation

Drugs	Ref.	Derivatives	Notation
Acetanilide	[3,4]	1	Antipyretic
Acetohexamide	[1,3,4]	8	Diabetes II
Captopril	[1,3]	8	Cardiovascular
Cisplatin	[1-4]	2	Cancer
Diethylstilbestrol	[3,4]	1	Hormonal
Digoxin	[1,3]	4	Cardiovascular
Ergotamine	[1-3]	6	Cardiovascular
Ephedrine	[3]	9	CNS
Griseofulvin	[3,4]	0	Antifungal
Heparin	[2-4]	4	Cardiovascular
Isoniazid	[3,4]	0	Antibiotic
Lidocaine	[3]	6	CNS
Lithium	[1-4]	0	CNS
Marinol	[3]	1	CNS
Mechlorethamine	[1-4]	5	Cancer
Mecillinam	[3]	1	Antibiotic
Methotrexate	[1,3]	1	Cancer
Nalidixic acid	[1,3]	8	Antibiotic
Nitroglycerine	[1,3,4]	2	Cardiovascular
Penicillin	[1-4]	21	Antibiotic
Pentamidine	[3]	0	Antiprotozoal
Physostigmine	[3]	0	Ocular
Quinine	[3]	1	Antiprotozoal
Sorafenib	[1]	0	Cancer
Streptomycin	[1,2]	7	Antibiotic
Sulfanilamide	[1-3]	13	Antibiotic
Valproic acid	[3,4]	1	CNS
Vinblastine	[1-3]	3	Cancer
Dicoumarol	[2-4]	0	Cardiovascular
Warfarin	[2-4]	3	Cardiovascular
Zinc sulfate	[3]	0	Wilson’s disease

CNS: Central nervous system.

Table 5 List of drugs found to be beneficial for conditions other than for which they were developed (clinical), the number of identified derivatives and their therapeutic notation

Clinical drugs	Ref.	Derivatives	Notation
Aminoglutethimide	[3,4]	0	Cancer
Alprostadil	[3]	4	Cardiovascular
Amphetamine	[1,3,4]	10	CNS
Aspirin	[1-3]	0	Cardiovascular/Cancer
Auranofin	[2,3]	0	Antirheumatic
Carbamazepine	[3]	1	CNS
Celecoxib	[2]	0	Cancer
Chlordiazepoxide	[1-4]	20	CNS
Chlorothiazide	[1,3,4]	11	Diuretic
Clofibrate	[3]	1	Cardiovascular
Dactinomycin	[3]	0	Cancer
Diisopropylfluorophosphate	[3]	0	Ocular
Diltiazem	[3]	0	Cardiovascular
Dimenhydrinate	[2-4]	0	CNS
Diphenhydramine	[3]	2	CNS
Diphenoxylate	[3,4]	1	Antidiarrheal
Dipyridamole	[3]	0	Cardiovascular
Disulfiram	[1,2,4]	0	Alcoholism treatment
Doxorubicin	[3]	5	Cancer
Etomidate	[3,4]	0	CNS
Finasteride	[2]	1	Baldness
Guanethidine	[3,4]	2	Cardiovascular
Haloperidol	[1,3,4]	1	CNS
Imatinib	[1]	0	Cancer
Imipramine	[1-4]	10	CNS
Iproniazid	[1-4]	1	CNS
Linezolid	[1]	0	Antibiotic
LSD	[1-4]	5	CNS
Meprobamate	[2,4]	1	CNS
Mercaptopurine	[1,3]	2	Immunosuppressive
Metronidazole	[3]	1	Antiprotozoal
Mifepristone	[3,4]	0	Hormonal
Minoxidil	[2]	0	Cardiovascular
Mycophenolic acid	[3]	1	Immunosuppressive
Naloxone	[3]	1	CNS
Norethindrone	[1,3,4]	11	Hormonal
Pethidine	[3,4]	1	CNS
Phenobarbital	[3]	6	CNS
Prednisone	[3,4]	6	Anti-inflammatory
Probenecid	[2]	0	Gout
Procarbazine	[3]	0	CNS
Promethazine	[1-3]	20	Antihistamine
Quinacrine	[3]	4	Antiprotozoal
Reserpine	[1-3]	2	CNS
Salicyclic acid	[3]	4	Antirheumatic
Sildenafil	[1-3]	2	Erectile dysfunction
Sirolimus	[3]	1	Immunosuppressive
Tamoxifen	[1-4]	1	Cancer
Terfenadine	[3]	1	Antihistamine
Thalidomide	[1,2]	1	Cancer
Tolazoline	[3]	0	Cardiovascular
Trimethadione	[3]	1	CNS
Zidovudine	[1,2]	5	Antiviral

CNS: Central nervous system; LSD: Lysergische säure diäthylamid (lysergic acid diethylamide).